I-Mab
NasdaqGM:IMAB
$ 1.80
$-0.07 (-3.78%)
$ 1.80
$-0.07 (-3.78%)
Real-time: 03/01/2024 14:43

About I-Mab

I-Mab and its subsidiaries principally engage in discovering and developing transformational biologics in the fields of immuno-oncology and immuno-inflammation diseases in the People's Republic of China (the 'PRC') and other countries and regions. I-Mab share price history

Drug Pipeline

The company's advanced drug pipeline is led by five key clinical assets, followed by the next-generation bi-specific antibody assets. The section below describes the development status of the key clinical assets and selected pre-clinical assets.

Five Key Clinical Assets

Eftansomatropin alfa (TJ101): A Differentiated Long-Acting Growth Hormone for Pediatric Growth Hormone Deficiency

Eftansomatropin alfa is a differentiated long-acting recombinant human growth hormone (rhGH) developed for pediatric growth hormone deficiency (PGHD), being the only rhGH in its proprietary fusion protein format and is not chemically linked with PEG or other linkers. Its safety, tolerability, and efficacy have been well demonstrated in Phase 1 and Phase 2 clinical trials. The company is progressing towards the end of a Phase 3 registrational trial ('TALLER') of eftansomatropin alfa as a weekly treatment for PGHD patients in China, with plans to submit an NDA by the end of 2023 or early 2024. The company obtained the rights from Genexine for the development, manufacturing and commercialization of eftansomatropin alfa in China. In November 2021, the company entered into a strategic commercial partnership with Jumpcan, a leading domestic pharmaceutical company specializing in and committed to pediatric medicines, to accelerate the commercialization of eftansomatropin alfa. I-Mab share price history

Mechanism of Action

Eftansomatropin alfa is based on Genexine's patented hyFc technology. The hyFc part consists of a portion of human immunoglobulin D ('IgD') and G4 ('IgG4'). The former contains a flexible hinge, and the latter is responsible for half-life extension through neonatal Fc receptor ('FcRn')-mediated recycling. Additionally, eftansomatropin alfa's increased molecular weight (103 kilodaltons) is expected to reduce renal clearance.

Summary of Clinical Results

Genexine has completed three clinical trials with eftansomatropin alfa, including one Phase 1 trial in healthy adult volunteers, one Phase 1b/2 multi-regional trial in adults with GHD, and one Phase 2 multi-regional trial in PGHD in Europe, altogether involving 32 healthy subjects and 99 patients with GHD and PGHD. Overall, eftansomatropin alfa was shown to be well-tolerated, and the clinical efficacy endpoint achieved by weekly or twice-monthly eftansomatropin alfa administration was comparable to that of daily administration of Genotropin.

Phase 1 Clinical Trial in Healthy Adult Subjects

The first-in-human trial of eftansomatropin alfa was a randomized, double-blind, placebo-controlled single dose-ascending study in four groups of healthy subjects. A total of 32 subjects were enrolled, and 31 completed the study. Eftansomatropin alfa was shown to be well-tolerated at all dose levels studied (0.2-1.6 mg/kg). Eftansomatropin alfa was detectable in the blood until Day 7 for the 0.2 mg/kg dose group, Day 14 for the 0.4 and 0.8 mg/kg dose groups, and Day 21 for the 1.6 mg/kg dose group. A single subcutaneous ('SC') injection of eftansomatropin alfa at dose levels of 0.4 mg/kg and higher increased IGF-1 and IGF -binding protein-3 ('IGFBP-3') levels for at least one week. No safety concerns were identified. Eftansomatropin alfa showed a half-life ranging from 69.2 to 138 hours.

Phase 2 Clinical Trial in PGHD

The Phase 2 trial in PGHD was a randomized, open-label, active-controlled study to assess the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of weekly and twice-monthly doses of eftansomatropin alfa, as compared with a daily injection of Genotropin, the current standard of care for PGHD. The primary clinical endpoint was annualized height velocity (aHV) in centimeters (cm) per year (equivalent to annual growth rate), measured at six months. A total of 56 subjects were randomized at 27 centers in nine European countries and South Korea.

Registrational Phase 3 Clinical Trial

The registrational Phase 3 trial of eftansomatropin alfa in PGHD ('TALLER') is on track in China. In May 2022, the company announced the completion of patient enrollment in the TALLER study for the treatment of PGHD. TALLER is a multi-center, randomized, open-label, active-controlled clinical study designed to assess the efficacy, safety, and pharmacokinetics of eftansomatropin alfa in PGHD (NCT04633057). Following the completion of the patient enrollment, the final dataset from the TALLER study is anticipated in the second half of 2023, which is expected to be followed by an NDA submission by the end of 2023 or early 2024.

In November 2021, the company announced a strategic commercial partnership with Jumpcan, a leading domestic pharmaceutical company specializing in and committed to pediatric medicines, to accelerate the commercialization of eftansomatropin alfa. The company will be the marketing authorization holder (MAH) of the product and supply the product at an agreed cost to Jumpcan. Jumpcan will be responsible for commercializing the product and developing new indications in collaboration with the company in mainland China. In addition, I-Mab and Jumpcan will share profits generated from the commercialization of the product in mainland China on a 50/50 basis, pursuant to which the company will be entitled to receive tiered low double-digit royalties on net sales. This partnership deal represents one of the largest in China's biopharma market to date. Both companies have been working together to prepare for the future product launch of eftansomatropin alfa in China.

Felzartamab (TJ202): A Differentiated CD38 Antibody for Multiple Myeloma and Autoimmune Diseases

Felzartamab is a differentiated CD38 antibody for the treatment of relapsed and refractory multiple myeloma (MM) and potentially autoantibody-mediated autoimmune diseases. The company obtained the rights from MorphoSys to develop, manufacture, and commercialize felzartamab in Greater China. Clinical data available from MorphoSys and I-Mab confirmed the advantages of felzartamab in its lower infusion-related reaction rates and a shorter infusion time, making felzartamab's use in an out-patient clinic setting possible, along with other potential benefits.

The company is on track with the registrational trial of felzartamab in combination with lenalidomide and dexamethasone as a second-line (2L) MM treatment. The topline data package, when fully matured, is expected to support the company's NDA submission.

In January 2022, the company signed a partnership agreement with the government of Qiantang District of Hangzhou in China to manufacture felzartamab locally to accelerate the company's commercialization of felzartamab.

Mechanism of Action

Felzartamab binds to CD38 overexpressed on the surface of target cells and kills them by inducing antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The target cells are the malignant plasma cells in MM and a group of dysregulated CD38 high B cells and plasma cells that produce pathogenic antibodies in autoimmune conditions, such as SLE.

Summary of Clinical Results

Phase 1/2a Trial in patients with r/r MM by MorphoSys

A Phase 1/2a, open-label, multicenter, dose-escalation study in adult patients with relapsed or refractory MM was conducted by MorphoSys in Austria and Germany. The results concluded that felzartamab was well-tolerated as a single agent and in combination with dexamethasone (DEX), pomalidomide (POM)/DEX, or lenalidomide (LEN)/DEX. Felzartamab was administered as a two-hour IV infusion at the first dose, and infusion time could be reduced to as short as 30 minutes at subsequent doses without obvious safety concerns. The maximal tolerable dose (MTD) of felzartamab was not reached.

Clinical Development Status

The third-line MM registrational trial has been completed, and the topline data have met the preset primary and secondary endpoints. More importantly, the clinical data have confirmed the clinical advantages of felzartamab in terms of lower infusion-related reaction rate and shorter infusion time, which makes it feasible and practical for its use in an out-patient clinic setting.

For the registrational trial of felzartamab and lenalidomide/dexamethasone as a 2L MM treatment, the company completed patient enrollment in September 2021. The topline data package, when fully matured in 2023, is expected to support an NDA submission.

The company plans to position felzartamab as the first and only locally manufactured CD38 antibody in China to facilitate its potential NDA submission and to be more commercially competitive. With the support of the local government in China, the company's plan is to manufacture felzartamab locally for increased affordability and commercial competitiveness. In parallel, the company is exploring commercial partnerships in China for felzartamab, with the goal of enabling the company to quickly gain and scale up market share for felzartamab without investing significant resources in the company's own commercialization capabilities.

Lemzoparlimab (TJC4): A Novel CD47 Antibody for Immuno-Oncology with First-in-Class Potential in China

Lemzoparlimab is a fully human CD47 monoclonal antibody discovered and developed internally by the company's company for cancer immunotherapy. CD47 has emerged as one of the most promising immuno-oncology targets in recent years. Lemzoparlimab is among the global front-runners after magrolimab. As one of the most promising drug classes in immuno-oncology, the development of CD47 antibodies is primarily hampered by their on-target binding to red blood cells (RBCs). Therefore, various CD47 antibodies in their clinical development are found to be susceptible to severe anemia and other hematologic side effects. As a result, many CD47 antibody programs have been either terminated in early clinical trials or faced drug safety challenges in clinical trials. For example, in January 2022, Gilead announced that the U.S. FDA had placed a partial clinical hold on studies evaluating the combination of magrolimab plus azacitidine due to an apparent imbalance in investigator-reported suspected unexpected serious adverse reactions (SUSARs) between study arms, which was later lifted for the study in acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) but remained in diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM).

Lemzoparlimab is a novel CD47 antibody by design. It was originally selected from antibody screen campaigns designed to identify CD47 antibody leads with minimal binding to RBCs while maintaining strong binding to tumor cells. In terms of its differentiation in drug safety, the preclinical, Phase 1, and Phase 2 clinical studies the company conducted so far have supported a good safety profile without the need for a priming dosing regimen. In terms of treatment efficacy, the company's Phase 1 and Phase 2 clinical trials have demonstrated encouraging efficacy signals, mostly in hematologic malignancies. In September 2022, the company presented the Phase 2 clinical data (NCT04202003) of lemzoparlimab in combination with AZA in patients with newly diagnosed higher risk myelodysplastic syndrome (HR-MDS) at the European Society for Medical Oncology (ESMO) Congress. Furthermore, the company will provide the updated data from the Phase 2 MDS trial in the second half of 2023.

The company's clinical development plan is aimed to prioritize hematologic malignancies with the first-line (1L) MDS combination therapy with azacitidine (AZA) as a lead indication. A Phase 3 clinical trial for 1L MDS combination therapy has been initiated in April 2023. Additionally, the company is progressing towards the end of a Phase 2 AML trial in combination with AZA, and continues to evaluate lemzoparlimab in combination with rituximab in patients with non-Hodgkin's lymphoma (NHL) and with PD-1 therapy in patients with selected solid tumors.

Molecular Differentiation of Lemzoparlimab

Lemzoparlimab exhibits high-affinity binding to human CD47 protein and CD47-expressing tumor cells at the nanomolar level and effectively blocks the interaction of CD47 with its receptor SIRPalpha. As compared with other CD47 antibodies under clinical development, lemzoparlimab (TJC4) demonstrated comparable potency in the enhanced macrophage-mediated phagocytosis of Raji tumor cells and anti-tumor activity in the HL-60 cell line in leukemia and Raji xenograft models. Moreover, when combined with rituximab, lemzoparlimab exhibited a markedly enhanced inhibition of tumor growth in a diffuse large B cell lymphoma (DLBCL) animal model through the synergistic effect of both agents.

The Underlying Mechanism for Lemzoparlimab's Differentiation

The company sets forth to investigate the molecular mechanism underlying the minimal binding of lemzoparlimab to RBCs. The crystal structure of the CD47 antibody binding complex revealed that lemzoparlimab binds to a unique epitope of CD47 situated in a heavily glycosylated site on RBCs.

Amendment to the Global Partnership with AbbVie

In August 2022, the company entered into an amendment with AbbVie Global Enterprises Ltd. (as assignee of AbbVie) to the original collaboration agreement (as amended, the 'AbbVie Collaboration Agreement'). The parties are collaborating on the global development of certain new anti-CD47 antibodies under the AbbVie Collaboration Agreement. The company has the exclusive right to develop and commercialize all licensed products under the AbbVie Collaboration Agreement in Greater China. Meanwhile AbbVie discontinued the global Phase 1b study of lemzoparlimab combination therapy with AZA and venetoclax, in patients with MDS and AML, and a Phase 1b study of lemzoparlimab in patients with relapsed/refractory multiple myeloma. These discontinuations were not related to any specific or unexpected safety concerns.

Summary of Clinical Results

Drug Safety

In terms of lemzoparlimab's safety profile, after the announcement of magrolimab's partial clinical hold in 2022, the company conducted a systemic review of the safety data collected from nearly 200 patients, including solid tumors and hematologic malignancies treated in various combinations. The safety data from both the U.S. and China studies are consistent with the company's expected safety profile without the need of a priming dose regimen. As a result, there is no change in the company's strategy and plans for the development of lemzoparlimab.

For the studies in solid tumors and NHL in the U.S., lemzoparlimab was well tolerated up to 30 mg/kg on a weekly infusion schedule without priming dosing either in mono- or combination therapy. A MTD was not reached. All treatment-related adverse events (TRAEs) were either Grade 1 or Grade 2, except that one Grade 3 lipase increase was reported in the single-agent dose-escalation study in solid tumors and one Grade 3 TRAEs from the same patient, including pleural effusion, tachycardia, cough, pruritis, fatigue, rash, and dyspnea, at 20 mg/kg dose in a combination study with rituximab in NHL. No clinical or laboratory evidence of hemolytic anemia was observed throughout. The hematological data from both studies in solid tumors and NHL showed a transient reduction in the hemoglobin levels during the first cycle. The average drop was approximately 10% and was not dose-dependent. This finding is consistent with the results of preclinical GLP toxicity studies. None of the drug-related anemia reported was considered to be severe or hemolytic in nature.

For the Phase 2 clinical trial in AML/MDS, over 90 patients were dosed with lemzoparlimab at 30 mg/kg in combination with AZA in China. The safety data are being analyzed for a subsequent topline data release.

Clinical Efficacy

Across multiple completed and ongoing clinical trials, encouraging efficacy signals were observed and described below.

For lemzoparlimab monotherapy in patients with solid tumors, one confirmed Partial Response (PR) was observed in the 30 mg/kg monotherapy cohort (1/3). The patient who had metastatic melanoma had failed prior systemic treatment of nivolumab and ipilimumab. In addition, three patients achieved Stable Disease (SD) with SD duration longer than 16 weeks at dose cohorts of 1 mg/kg, 10 mg/kg, and 30 mg/kg. Two patients with squamous cell carcinoma of the head and neck (SCCHN) and renal cell carcinoma (RCC), respectively, failed nivolumab and the other with ovarian cancer received no prior PD-(L)1 inhibitor treatment.

For lemzoparlimab combination therapy with rituximab in patients with NHL, the company presented interim dose escalation data of lemzoparlimab in combination with rituximab in relapsed and refractory (r/r) NHL at the 2021 American Society of Hematology (ASH) Annual Meeting. The preliminary data were generated from nine patients with r/r NHL who received at least two prior lines of therapies, with a median of four lines. Safety findings of lemzoparlimab at doses of 20 mg/kg and 30 mg/kg weekly, without a priming dose, are consistent with what was observed at lower doses, and no dose-limiting toxicity (DLT) was observed. Positive clinical activity was observed in heavily pretreated patients who had progressed on prior anti-CD20 therapies. Among seven efficacy-evaluable patients, four achieved complete responses (CR) (1 transformed FL-DLBCL +3 FL), one partial response (PR) of FL were observed (ORR = 71%); two reported stable disease (SD), and the disease control rate (DCR) was 100%. Tumor shrinkage was observed in all evaluable patients. The median time to response was 50 days, and the response lasted from 61 to 236 days. A high level (80% and 90%) of intra-tumoral distribution measured by IHC of tumor biopsy was reached at 20 mg/kg and 30mg/kg weekly.

For lemzoparlimab combination therapy with AZA in patients with MDS, over 90 patients with newly diagnosed MDS and AML were dosed in the Phase 2 clinical trial of lemzoparlimab at 30 mg/kg in combination with AZA in China (NCT04202003). This patient cohort had a more severe disease at baseline due to disease conditions and clinical practice patterns in China. In September 2022, the company announced encouraging data from this Phase 2 clinical trial in patients with newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS), presented in an oral presentation at ESMO 2022. A total of 53 patients were enrolled as of March 31, 2022, receiving lemzoparlimab at a weekly dose of 30 mg/kg intravenously (IV) and AZA at 75 mg/m2 subcutaneously (SC) on Days 1-7 in a 28-day cycle. Top-line data showed that for patients who began treatments 6 months or longer prior to the analysis (n=15), the overall response rate (ORR) and complete response rate (CRR) were 86.7% and 40%, respectively. Updated results from the most recent data analysis of 62 patients in the study have demonstrated consistent clinical efficacy, including ORR and CRR with no new safety signals identified. The company plans to present the updated data at a major scientific meeting in the second half of 2023.

Clinical Development Plan

Leukemia. The company is advancing its Phase 3 registrational trial of lemzoparlimab combination therapy for potential 1L treatment of newly diagnosed HR-MDS after approval by the CDE in September 2022. The company presented the full dataset of its Phase 2 clinical trial in patients with newly diagnosed HR-MDS at the ESMO 2022 in September 2022 and expect to present the updated data readout of this study in the second half of 2023.

Lymphoma and Solid Tumors. The company previously presented the encouraging clinical data at the 2021 American Society of Hematology (ASH) annual meeting for lemzoparlimab combination therapy with rituximab in patients with NHL. The company continues to evaluate lemzoparlimab in combination with rituximab in patients with NHL and with PD-1 therapy in patients with selected solid tumors. More data will be reported as the studies progress.

Uliledlimab (TJD5): A Highly Differentiated CD73 Antibody for Solid Tumors

Summary

Uliledlimab is an internally discovered, highly differentiated CD73 neutralizing antibody. CD73 is a homodimeric enzyme widely expressed in multiple tumors and plays a critical role in the generation of adenosine to contribute to an immuno-suppressive tumor microenvironment. The key differentiation of uliledlimab, when compared to some of the other clinical-stage CD73 antibodies, is related to its novel epitope, which works through a unique intra-dimer binding mode, resulting in complete inhibition of the enzymatic activity and avoiding the aberrant pharmacological property known as the 'hook effect.' In addition, uliledlimab has a non-competitive inhibitory effect that is not blunted by high levels of CD73 enzyme substrates, which would be expected for small-molecule competitive blockers. Preclinical studies have shown that uliledlimab could completely reverse the AMP-or tumor cell-mediated suppression of T cells in vitro. When combined with a PD-(L)1 antibody in vivo, uliledlimab exhibited a superior and synergistic inhibitory effect on tumor growth compared to PD-(L)1 monotherapy.

Uliledlimab is globally competitive and is among the front-runners after oleclumab, with significant progress made in its global clinical development. In the U.S., the company has completed the initial assessment of a Phase 1 clinical study where uliledlimab was evaluated as a monotherapy lead-in and followed by combining with atezolizumab (Tecentriq) in patients with solid tumors. Topline results from this study showed that uliledlimab is safe and well-tolerated across all the dose cohorts evaluated. The data demonstrated a favorable linear PK and steep PK/PD relationship with complete receptor occupancy as expected based upon the normal dose-response property of uliledlimab without the hook effect. Furthermore, encouraging clinical efficacy signals from this study were observed in NSCLC and ovarian patients with higher CD73 and PD-L1 co-expression in the tumor, indicating a potential correlation between the clinical activity of uliledlimab and tumor CD73 expression as a potential predictive biomarker that warrants further investigation.

Based on the results of the Phase 1 study, the company was able to determine the recommended phase 2 dose (RP2D) and further evaluated the efficacy and safety of uliledlimab in combination with checkpoint inhibitor in Stage IV NSCLC and other select tumor types in Phase 2 trials. The most encouraging results came from the company's Phase 2 trial of uliledlimab in combination with toripalimab (TUOYI) in patients with Stage IV NSCLC. Since the initial presentation at the 2022 American Society of Clinical Oncology (ASCO) annual meeting, the company has completed the enrollment of 70 patients in December 2022. Similar efficacy data in relation to CD73 expression were obtained with increased follow-up time in more patients, showing a consistent trend of efficacy signals with an overall ORR >30% in all patients and, noticeably, an ORR ~50% in CD73 high expression patients. The results have demonstrated that the higher clinical response of uliledlimab and PD-1 combination therapy correlates with high tumor CD73 expression in patients with advanced NSCLC. The company plans to present the data at the ASCO 2023 annual meeting. With the availability of the new data, the company has been actively discussing with potential global partners and aim to accelerate the ongoing business discussion for a potential global partnership.

Competitive Landscape

The most advanced CD73 antibody is oleclumab (MEDI-9447) from Medimmune/AstraZeneca, which has initiated a Phase 3, double-blinded, placebo-controlled, randomized study of durvalumab plus oleclumab in patients with locally advanced (Stage III), unresectable NSCLC who have not progressed following definitive, platinum-based concurrent chemoradiation therapy. Data from the COAST Phase 2 trial and NeoCOAST Phase 2 trials showed that the addition of oleclumab to durvalumab enhanced anti-tumor immune responses in patients with NSCLC. NZV-930 (from Novartis) and AK119 (from AkesoBio) were in Phase 1 clinical development for solid tumors. Arcus Biosciences had also reported promising results in their Phase 1b/2 trial of quemliclustat, a small molecule CD73 inhibitor, in combination with zimberelimab plus chemotherapy in patients with pancreatic cancer.

Molecular Differentiation of Uliledlimab

Biochemically, uliledlimab displayed complete inhibition of soluble CD73 enzymatic activity (IC50 = 0.22 n M) without the 'hook effect' in contrast to the comparator molecule, which at higher concentrations caused a paradoxical rebound of enzymatic activity presumably due to its inter-dimer binding mode. The recent structural data revealed by cryo-EM showed that uliledlimab binds to a unique epitope located at the C-terminus of CD73 dimer distinct from other CD73 antibodies, including oleclumab, all of which bind to the N-terminus of CD73. With this unique epitope, uliledlimab adopts a differentiated intra-dimer binding mode to prevent the conformational change of CD73 from inactive to the active form, resulting in the complete inhibition of CD73 enzymatic activity without causing a 'hook effect.'

Consistent with the in vitro results, in vivo monotherapy of uliledlimab dose-dependently inhibited in situ tumor-derived CD73 activity, leading to the anti-tumor effect in a mouse xenograft model bearing A375 melanoma cells. To examine whether uliledlimab could enhance the anti-tumor activity of PD-1 or PD-L1 antibodies, the company evaluated the therapeutic effects of uliledlimab in combination with a PD-1 antibody in the MC38 model using CD73 humanized mouse and PD-L1 antibody in the A375 xenograft model, respectively. The combination treatments resulted in more potent inhibition of tumor growth than monotherapy of PD-(L)1 antibody or uliledlimab.

Summary of Clinical Results

Phase 1 dose-escalation study in combination with atezolizumab

Data from the U.S. Phase 1 dose-escalation study of uliledlimab in combination with atezolizumab, which were presented at the 2021 ASCO annual meeting, showed that uliledlimab is safe and well-tolerated with no dose-limiting toxicity across all the dose cohorts in combination with atezolizumab. All treatment-related adverse events were either Grade 1 or Grade 2. Uliledlimab demonstrated a linear PK profile and reached full receptor occupancy on B cells at the middle and high dose levels with no 'hook effect,' confirming a normal PK/PD relationship and sigmoid dose-activity response.

Phase 2 clinical study of uliledlimab in combination with PD-1 antibody (toripalimab) in advanced NSCLC

In May 2022, the company presented the preliminary clinical results of an ongoing phase 2 clinical study of uliledlimab in combination with toripalimab (TUOYI) in patients with NSCLC at the 2022 ASCO annual meeting. The results are largely consistent with those observed in first-in-human Phase 1 clinical trial in relation to favorable safety, pharmacokinetics (PK), and pharmacodynamic (PD) profile of uliledlimab. Uliledlimab can be safely administered and well-tolerated up to the highest doses tested at 30 mg/kg Q3W, as a monotherapy and as a combination therapy with toripalimab with no dose limiting toxicity (DLT). Uliledlimab exhibited a linear PK profile at doses greater than or equal to 5mg/kg and a dose-dependent receptor occupancy with no 'hook effect' where the antibody loses its effectiveness at high concentrations.

As of December 2022, 70 patients had been enrolled in the same Phase 2 study of uliledlimab and PD-1 combination therapy in Stage IV NSCLC patients who were previously ineligible for standard-of-care treatment.

Clinical Development Plan

Based on the role of CD73 as a predictive biomarker and encouraging clinical efficacy data based on approximately 70 advanced NSCLC patients, the company plans to initiate a biomarker-guided pivotal study evaluating clinical efficacy of the combination of uliledlimab and a PD-1 antibody in Stage IV NSCLC patients in the second half of 2023. Another global study of uliledlimab in combination with a PD-1 antibody plus a chemotherapy in patients with advanced NSCLC is also planned in the second half of 2023. In parallel, a standardized companion CD73 diagnostic kit is being developed with WuXi Diagnostics to be employed in the planned studies.

Givastomig (TJ-CD4B): A Novel, Tumor-Dependent T Cell Engager for Gastric and Other Cancers

Givastomig is a bi-specific antibody targeting both Claudin18.2 (CLDN18.2), a tumor antigen preferentially expressed in gastric and pancreatic cancers, and 4-1BB, a co-stimulatory molecule on T cells. CLDN18.2 is a tight junction molecule whose expression is normally restricted to epithelial cells of the gastric mucosa, but becomes widely expressed in select tumors (such as gastric and pancreatic cancers), making it a highly attractive tumor target.

In collaboration with ABL Bio, the company developed givastomig, also known as ABL111, which provides two key advantages over current CLDN18.2 antibodies and 4-1BB agonistic antibodies. Firstly, givastomig (also known as TJ033721) can bind to tumor cells even with low levels of CLDN18.2 expression, making it more suitable for a broader patient population with various expression levels of CLND18.2. Secondly, only upon tumor cell engagement by givastomig are T cells stimulated by the 4-1BB antibody moiety, making the 4-1BB antibody arm only active at the tumor site. This localized T cell activation is conditional upon tumor engagement and is expected to exert strong anti-tumor activity while minimizing systemic side effects such as liver toxicity seen with 4-1BB agents in previous clinical studies.

In November 2021, the company and ABL Bio jointly announced the pharmacodynamic data and safety of givastomig/ABL111 in animal models and cell cultures at the 2021 SITC annual meeting. The data are summarized as below: (1) Potent anti-tumor activity was observed with the proliferation of immune cells within the tumor microenvironment (TME), as well as an increase in memory T cells in the peripheral blood, suggesting long-term immunity against the tumor; (2) Givastomig was well tolerated in non-human primates and did not induce a systemic immune response or liver toxicity up to levels of 100 mg/kg; and (3) Activation of immune pathways by givastomig was demonstrated by a pro-inflammatory profile and increased gamma interferon-regulated gene expression in primary human CD8+ T cells co-cultured with CLDN18.2 expressing cells. In March 2022, the company announced that the U.S. FDA granted givastomig Orphan Drug Designation (ODD) for the treatment of gastric cancer, including gastroesophageal junction carcinoma.

Therapeutic Indications

Zolbetuximab is a CLDN18.2 monoclonal antibody acting through ADCC and CDC. It has demonstrated clinical efficacy (and thus target validation) when combined with standard chemotherapy in early clinical trials. However, the efficacy of zolbetuximab is limited to CLDN18.2 high-expressing tumors (expression cutoff 75%); and (2) Antibody-drug conjugates (ADCs), CAR-Ts, and CD3-based bispecific T cell engagers. Most of these studies are either at pre-clinical stage or early clinical development. Despite their anticipated high efficacy, these treatment modalities suffer from significant safety concerns associated with their drug toxicity or immunotoxicity.

Summary of Clinical Results

Phase 1 clinical trial of givastomig in patients with advanced or metastatic solid tumors:

The dose escalation part of the study reached 15 mg/kg without encountering dose limiting toxicity (DLT). By the end of 2022, eight dose cohorts had been completed, with 38 subjects dosed. Givastomig was well tolerated, most of the treatment-related adverse events (TRAEs) were grade 1 or 2 and no DLTs were reported. There is a dose-dependent increase of drug exposure and soluble 4-1BB in serum, suggestive of a favorable PK/PD profile and potentially a longer dosing interval with durable T cell activation. Partial response (PR) and stable disease (SD) signals of givastomig monotherapy were observed across efficacious dose levels in gastric cancer patients who failed multiple lines of prior therapies, including PD-1 therapy. More encouragingly, efficacy signals were also observed in patients with low CLDN18.2 expression, indicating its potential to treat CLDN18.2 low-expressing tumors where other CLDN18.2 targeted agents have a limited treatment effect. The complete Phase 1 data is expected to be presented at a medical conference in the second half of 2023.

Clinical Development Plan

The company is accumulating and evaluating the Phase 1 data to determine the RP2D. More data from the ongoing study are anticipated in the second half of 2023. The clinical development plan is being finalized to initiate a Phase 2 study in the second half of 2023. In parallel, the company is developing a CLDN18.2 IHC assay for patient selection, which will be used in the company's future clinical studies. Furthermore, the company is in the process of exploring potential global partnership opportunities for givastomig.

Other Clinical Assets

TJ-L14B: A PD-L1-Based Tumor-Dependent T-Cell Engager for Solid Tumors

TJ-L14B, also known as ABL503, is a bi-specific antibody targeting both PD-L1 and 4-1BB and was developed in collaboration with ABL Bio. It was designed to overcome the limited efficacy of anti-PD-(L)1 and anti-4-1BB-related toxicity. Similar to givastomig, 4-1BB-stimulated T cell activity only occurs upon tumor cell binding by the anti-PD-L1 part of TJ-L14B. This localized T cell activation is expected to exert strong anti-tumor activity while reducing systemic side effects such as liver toxicity. In a humanized mouse tumor model, a short course of TJ-L14B treatment displayed greater anti-tumor efficacy than anti-PD-L1 or anti-4-1BB alone or in combination and showed evidence of immunological memory response that resisted tumor re-challenge. GMP material at 1000-L scale was successfully produced. In January 2021, the company received IND approval from the U.S. FDA for a Phase 1 study of TJ-L14B and dosed the first patient in April 2021. The company shares the global rights with ABL Bio for TJ-L14B, except for in Greater China and South Korea where ABL Bio has sole rights.

Therapeutic Indications

As previously stated, new therapeutic options are urgently needed for PD-(L)1 relapsed or refractory cancer patients. One strategy is to maximize T cell activity by simultaneously turning off co-inhibitory pathways, such as PD-1/PD-L1 and turning on co-stimulatory pathways, such as 4-1BB, which is one of the most potent T cell potentiators, as indicated earlier in this document. Several companies have been developing PD-L1 x 4-1BB bi-specific antibodies, with the most advanced being developed by Genmab and Inhibrx, which are both in Phase 2 trials.

Summary of Preclinical Results

PD-L1 level-dependent 4-1BB Agonism and T Cell Activity. The ability of TJ-L14B to ligate 4-1BB and activate downstream signaling was tested in a co-culture of PD-L1+ target cells with T cells as effectors. The results in the figure show that the level of NF-kB reporter activity elicited by TJ-L14B correlated with the level of PD-L1 expression on the target cells. In contrast, urelumab induced NF-kB reporter activity regardless of target cell PD-L1 expression. Importantly, TJ-L14B promoted the proliferation of CD8+ tumor-infiltrating lymphocytes obtained from human tumor samples in a similar extent to urelumab, while the parental anti-PD-L1 and anti-4-1BB antibodies, either alone or in combination, had no effect, confirming a strict PD-L1-dependence on T cell stimulation by TJ-L14B.

Clinical Development Plan

Phase 1 dose-escalation and dose-expansion study of TJ-L14B is ongoing in patients with progressive locally advanced or metastatic solid tumors who are relapsed or refractory following prior lines of treatment with no available treatment options. The dose escalation has reached an efficacious dose level. TJ-L14B was well tolerated, and MTD was not reached. Clinical PK data indicated a linear dose profile and early clinical efficacy signals were observed. The dose expansion part of TJ-L14B will be initiated in the second half of 2023, both in the U.S. and Korea. The trial is being conducted by the company's partner ABL Bio. More data will be generated as the trial progresses.

Efineptakin alfa (TJ107): The World's First and Only Long-acting Recombinant Human IL-7 for Cancer Treatment-related Lymphopenia and Cancer Immunotherapy

Summary

Efineptakin alfa is the world's first and only long-acting recombinant human interleukin-7 ('rhIL-7'), which is being developed as a T lymphocyte-booster for cancer-related immunotherapy. This Phase 2 clinical-stage asset is positioned as a monotherapy for the treatment of cancer patients with lymphopenia because of its unique properties of increasing anti-tumor T cell numbers and as combination immunotherapy with a PD-1 or PD-L1 antibody because of its potential synergism with PD-1/PD-L1 therapy. The company obtained the rights from Genexine for the development, manufacturing and commercialization of efineptakin alfa in Greater China.

Efineptakin alfa has an advantage over other T lymphocyte cytokines with its therapeutic potential in oncology. Preclinical and clinical results generated so far indicate that efineptakin alfa has a selective and favorable immune function profile over recombinant human interleukin-2 (rhIL-2) in that efineptakin alfa activates and expands tumor-attacking CD4, CD8, and natural killer T cells, but spares tumor-protecting Treg cells.

The company is running two Phase 2 clinical trials for the development of efineptakin alfa in China. In January 2022, the first patient was dosed in a Phase 2 study of efineptakin alfa in combination with pembrolizumab (Keytruda) in patients with advanced solid tumors. The study follows a 'basket' trial design to include selected tumor types, including triple-negative breast cancer (TNBC) and squamous cell cancer of the head and neck (SCCHN). The other Phase 2 trial is on track in patients with newly diagnosed glioblastoma multiforme (GBM) with standard concurrent chemoradiotherapy.

Mechanism of Action

IL-7 is a cytokine essential for the survival and homeostatic proliferation of naive and memory T cells. IL-7 is critically involved in restoring T cells to normal levels in the event of lymphopenia by stimulating T cell proliferation. It exerts its functions by binding to and activating the IL-7 receptor, which is expressed primarily on lymphocytes, including the lymphoid precursors, developing T and B cells, naive T cells, and memory T cells, but not on tumor-protecting Tregs. Efineptakin alfa as a monotherapy may enhance anti-tumor immunity by augmenting the number and functionality of T cells. Moreover, efineptakin alfa in combination with an immune checkpoint inhibitor, cancer vaccine, or CAR-T may improve the anti-tumor response by restoring T cell numbers, reconstituting T cell pools, and reinvigorating exhausted T cells.

Therapeutic Indications

One of the target therapeutic indications of efineptakin alfa is cancer treatment-related lymphopenia. Cancer patients who undergo chemotherapy and/or radiation therapy often develop cancer treatment-related lymphopenia, further damaging their already compromised immune systems and ability to fight against cancers. Advanced solid tumors are another indication for efineptakin alfa as a combination therapy with PD-1 therapy. As more than 60% of cancer patients either do not respond or respond poorly to PD-1/PD-L1 therapies, there are intense attempts to identify an effective agent that can work synergistically with PD-1/PD-L1 therapies to increase the probability of treatment success. Efineptakin alfa is believed to provide such a treatment option, which is supported by preclinical reports that IL-7 exhibits a synergistic effect with PD-1/PD-L1 therapies in the treatment of cancers and by the clinical data reported by Genexine/NeoImmuneTech (see elsewhere in this section).

Summary of Clinical Results

Clinical Trials in cancer patients in China by I-Mab

The company has completed a Phase 1 clinical trial in China in patients with advanced solid tumors and presented the topline safety and PK/PD data at the 2021 Chinese Society of Clinical Oncology (CSCO) annual meeting in September.

Clinical Trials conducted in the U.S. by Genexine/NeoImmuneTech

Efineptakin alfa and pembrolizumab combination therapy for solid tumors. The data from NeoImmuneTech dose-escalation trial (NCT04332653) presented at ASCO 2021 showed that MTD was not reached and efineptakin alfa was tolerable and safe in combination therapy with pembrolizumab in patients with advanced solid tumors.

Efineptakin alfa in combination with CAR-T therapy. In December 2022, NeoImmuneTech presented its recent data from an ongoing Phase 1b study evaluating safety, preliminary anti-tumor activity and T cell reconstitution with efineptakin alfa administered following tisagenlecleucel (Kymriah), a CD19-directed CAR-T therapy in patients with relapsed/refractory large B-cell lymphoma, at the 2022 American Society of Hematology (ASH) annual meeting. The data showed that efineptakin alfa treatment following tisagenlecleucel was safe and well-tolerated with no induction of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS), nor proinflammatory cytokines. Notably, efineptakin alfa treatment led to a sustained increase in ALC and increased CAR-T cell absolute numbers in the peripheral blood. Preliminary anti-tumor efficacy was also observed, particularly at dose level 3=240 µg/kg.

Clinical Development Plan

By leveraging the clinical results generated by Genexine/NeoImmuneTech so far, the company intends to advance the clinical development of efineptakin alfa for approvals in Greater China. The company's clinical development plan is focused on evaluating efficacy and safety of efineptakin alfa in cancer patients (1) as a broader oncology care treatment for those who suffer from lymphopenia commonly induced by chemotherapy and radiation therapy and (2) as a combination therapy with PD-1 therapy to achieve better clinical response and efficacy. A Phase 2 study (NCT05145907) has been initiated following a 'basket' trial design to include selected tumor types, including triple-negative breast cancer (TNBC) and squamous cell cancer of the head and neck (SCCHN). The first patient was dosed in the Phase 2 study of efineptakin alfa in combination with pembrolizumab (Keytruda) in patients with advanced solid tumors in January 2022.

TJ210/MOR210: A Novel C5aR1 Antibody for Cancers

TJ210 is a fully human, high-affinity antibody against human C5aR1 for the treatment of cancers. Certain tumors produce large amounts of complement factor C5a to attract C5aR1-expressing myeloid-derived suppressor cells ('MDSCs'), M2 macrophages, and neutrophils. These myeloid cells critically contribute to an immunosuppressive microenvironment as part of the evading mechanism of tumors and are associated with poor prognosis and resistance to PD-1/PD-L1 therapies in many cancers. TJ210 is designed to block the interaction between C5a and its receptor, thereby potentially neutralizing the immune suppressive function of C5a and enabling immune cells to attack the tumor.

Preclinical studies have shown that targeting the C5aR-C5a axis exerts anti-tumor activity with immune checkpoint inhibitors. Furthermore, in vitro activity was observed to block the C5a/C5aR pathway at very high C5a concentrations, leading to a long duration of action. TJ210 demonstrated a good safety profile with no observed adverse effects up to the highest dose tested in non-clinical safety studies. The in vitro and in vivo preclinical studies are ongoing to explore and validate the most effective combination partner(s) of TJ210 in addition to the PD-(L)1 antibody. The company obtained the rights from MorphoSys for the development, manufacturing and commercialization of TJ210 in Greater China and South Korea, and are co-developing the asset globally with MorphoSys.

Mechanism of Action

TJ210 is a C5aR-directed antagonist monoclonal antibody. C5aR (also known as C5aR1 or CD88) is a GPCR and is one of the two high-affinity receptors for its ligand, C5a. An extensive investigation of the TME has uncovered molecular mechanisms linking imbalanced complement activation and cancer progression. Upon activation, complement components, including C5a, are released into the TME, inducing the recruitment of immunosuppressive cells, including TAMs, TANs, MDSCs, Tregs, and DCs, thus inhibiting cytotoxic T-cell attack on the tumor. Immunosuppressive cytokines, such as Arg-1, IL-10, and TGF-ß, are also released. In addition, C5a can interact with its receptors to promote angiogenesis through upregulation of growth factors and enhancement of endothelial cell proliferation. C5a generation through an autocrine manner or intracellular protease from cleavage of C5 produced by tumor cells can act on the surface receptors and induce signaling pathways, such as PI3K-AKT, leading to the promotion of tumor cell adhesion, proliferation, migration, and stemness.

Therapeutic Indications

Traditionally regarded as the critical innate immune response, complement components, especially C5a/C5aR axis, have been demonstrated to be major contributors to immune suppression in the tumor micro-environment ('TME'), thereby disabling T cell function and promoting tumor progression. Correspondingly, blockade of C5a/C5aR signaling bears great potential for cancer immunotherapy in combination with immune check pointers or T cell engagers. High expression of C5aR in TME is correlated with poor diagnostic outcomes in various tumors, including colorectal carcinoma, renal cancer, gastric cancer, and a number of squamous carcinomas. In addition, activation of the complement cascade in those tumors either plays a critical role in cancer development or correlates with tumor grade and metastatic status.

Summary of Preclinical Results

TJ210 exerts strong anti-tumor activity by blocking the activation and migration of C5aR1-expressing myeloid cells and has the potential to be a differentiated agent as it binds to a novel epitope and possesses superior functional properties. Compared to the competitor antibody IPH5401 from Innate Pharma, TJ210 shows a more potent functional response, especially when C5a concentrations are high, indicating TJ210's potential at pathologic concentrations.

Clinical Development Plan

In September 2020, the U.S. FDA approved the company's IND to initiate a Phase 1 clinical trial to evaluate the safety, tolerability, MTD or maximum administered dose (MAD), PK and PD of TJ210. In January 2021, the company announced the dosing of the first patient in this trial, and patient recruitment for dose escalation was completed in the second quarter of 2022.

In June 2022, the company's partner MorphoSys entered into an equity participation and license agreements with Human Immunology Biosciences, Inc. ('HIBio'), a biotech company focusing on developing precision medicines for autoimmune and inflammatory diseases, for the development and commercialization of felzartamab and MOR210/TJ210 outside of Greater China. Under the terms of C5aR Agreement, the company obtained exclusive rights to develop and commercialize MOR210/TJ210 in Greater China and South Korea and share economics upon certain clinical milestones in the U.S.

Selected Preclinical Assets

TJ-C64B: A Novel Bi-Specific Antibody for Ovarian and Other Cancers

TJ-C64B is another bispecific molecule developed by leveraging the company's conditional 4-1BB platform, which has the advantage of minimizing systemic toxicities, i.e. liver toxicity, with an increased therapeutic window. It is specifically designed to simultaneously target Claudin6 (CLDN6), uniquely expressed in specific cancer types, including ovarian cancer cells, and engage 4-1BB through a unique conditional activation mechanism. CLDN6 is hardly detectable in normal adult tissues to ensure target specificity for ovarian cancers. In addition to the T cell activation through 4-1BB stimulation upon CLDN6 engagement, TJ-C64B has an added function of specifically depleting CLDN6-expressing tumor cells and intra-tumor regulatory T cells highly expressing 4-1BB, which differentiates it from other 4-1BB bispecific antibodies under clinical development. As published in AACR 2022, preclinical data showed that TJ-C64B enhances CLDN6-dependent T cell activation upon the engagement of cancer cell lines with different CLDN6 expression levels. In a syngeneic mouse model, TJ-C64B treatment induces strong anti-tumor activity with complete tumor regression in all tested mice at the dose of 4.5 mg/kg and durable resistance against tumor re-challenge through the immunological memory response. Further, ex vivo analysis confirms localized immune activation by TJ-C64B as evident by the increased CD8+ T cells in tumors.

The company has achieved candidate selection and are actively progressing the preclinical development of the candidate molecule.

TJ-L1IF: A Novel PD-L1/IFN-Alpha Antibody-Cytokine Fusion Protein Designed for PD-(L)1 Resistant Cancers

TJ-L1IF is a novel PD-L1/IFN-alpha antibody-cytokine fusion protein specifically designed for the treatment of PD(L)-1 resistant tumors through the addition of a strong immune adjuvant (interferon-alpha, IFN-alpha) to convert 'cold' tumor to 'hot' tumor on top of a PD-L1 antibody to achieve superior anti-tumor activity. Novel drug molecules with such a design are badly needed to address the current clinical challenges where a majority of cancer patients do not or poorly respond to PD-1/PD-L1 therapies. IFN-alpha was the first cytokine approved for cancer treatment, but its clinical use is limited by its systemic toxicities.

TJ-L1IF is composed of a PD-L1 antibody with an engineered IFN-alpha2b fused at the C-terminus of IgG. It is a prodrug in that the IFN-alpha2b moiety is masked by a PEG group through a protease-cleavable linker rendering the drug inactive in the circulation to avoid systemic toxicities. Once the drug accumulates at the tumor site through PD-L1 antibody targeting, the linker is cleaved by proteases that are highly expressed in the tumor environment to achieve specific activation only at the tumor site. This unique property of TJ-L1IF has been validated in a series of in vitro and in vivo studies, in which TJ-L1IF demonstrated good plasma stability, benign safety in cynomolgus monkeys, and superior anti-tumor activity in the PD-1/PD-L1 resistant tumor models as compared to PD-L1 antibody or IFN-alpha used either alone or in combination. After the first dose of treatment, the active format of the drug was quickly detected and accumulated in the tumor but not in the periphery, confirming the local delivery and conversion to an active form of IFN-alpha at the tumor site.

Licensing and Collaboration Arrangements

A. In-Licensing Arrangements

Licensing Agreement with MorphoSys (Felzartamab)

In November 2017, the company entered into a license and collaboration agreement with MorphoSys AG ('MorphoSys') with respect to the development and commercialization of felzartamab (MOR202/TJ202), MorphoSys's proprietary investigational antibody against CD38 (the 'CD38 product').

Under this agreement, MorphoSys granted to the company an exclusive, royalty-bearing, sublicensable license to exploit MOR202/TJ202 for any human therapeutic or diagnostic purpose in the licensed territory, namely Greater China.

Pursuant to this agreement, the company granted to MorphoSys an exclusive license to the company's rights in any inventions that the company makes while exploiting MOR202/TJ202 under this agreement, solely to exploit MOR202/TJ202 outside of Greater China.

The company also received the right to sublicense to affiliates and third parties acting as contract manufacturers, contract research organizations, distributors or wholesalers without prior written consent, as well as the right to sublicense to other third parties with the prior written consent of MorphoSys, not to be unreasonably withheld, delayed or conditioned.

The company is solely responsible for the development and commercialization of MOR202/TJ202 in Greater China, and must use commercially reasonable efforts as the company develop and commercialize MOR202/TJ202.

Assignment and License Agreement with Genexine

In October 2015, I-Mab Bio-tech Tianjin Co., Ltd., known as Tasgen Bio-tech (Tianjin) Co., Ltd. at the time (which subsequently became the company's subsidiary following the Acquisition) ('I-Mab Tianjin'), entered into an intellectual property assignment and license agreement with Genexine, Inc. ('Genexine'), further amended in December 2017, with respect to four licensed products, namely GX-H9 (TJ101), GX-G3 (TJ102), GX-G8 and GX-P2 and one assigned product, GX-G6 (TJ103). Under this agreement, Genexine (i) granted to I-Mab Tianjin an exclusive, non-transferable, sublicensable license to use and otherwise exploit certain intellectual property to engage in pre-clinical and clinical development, manufacturing, sale and distribution of the above-mentioned licensed products for (A) the treatment of any disease with respect to GX-H9 and GX-G3 in China (which, for clarity excludes, Hong Kong, Macau and Taiwan), (B) the treatment of chemically induced diarrhea, with respect to GX-G8 anywhere in the world and (C) the treatment of rheumatoid arthritis and lupus (not including psoriasis) with respect to GX-P2 anywhere in the world and further (ii) assigned to I-Mab Tianjin a certain Chinese patent and related know-how related to the assigned product (TJ103) and granted I-Mab Tianjin an exclusive license to exploit the assigned intellectual property to engage in pre-clinical and clinical development, manufacturing, sale and distribution of the assigned product (TJ103) for the treatment of any disease in China (which, for clarity, excludes Hong Kong, Macau and Taiwan). I-Mab Tianjin will also receive an exclusive license to any improvements that Genexine develops or acquires related to any of the aforementioned products.

In November 2018, the company entered into an intellectual property license agreement with Genexine with respect to GX-G3 (TJ102). Under this agreement, Genexine granted to the company an exclusive, non-transferable, sublicensable license to use and otherwise exploit certain intellectual property to engage in pre-clinical and clinical development, manufacturing, sale and distribution of GX-G3 for the treatment of any disease in Taiwan and Hong Kong. The company will also receive an exclusive license to use any improvements related to GX-G3 that Genexine develops or acquires free of charge in Taiwan and Hong Kong.

Licensing Agreement with Genexine (Efineptakin alfa)

In December 2017, the company entered into an intellectual property license agreement with Genexine with respect to GX-I7, a long-acting IL-7 cytokine. Under this agreement, Genexine granted to the company an exclusive, sublicensable and transferable license to use and otherwise exploit certain intellectual property (including improvements subsequently developed or acquired by Genexine) in connection with the pre-clinical and clinical development, manufacturing, sale and distribution of GX-I7 to treat cancers in the field of oncology in China, Hong Kong, Macau and Taiwan.

During the term of this agreement, if the company develops or acquires any improvement, modification or alteration to the licensed product, the company will own such improvements, modifications or alterations and provide Genexine details thereof, whether patentable or not. Additionally, the company should grant to Genexine a fully paid up, royalty-free, exclusive license (with a right to sublicense) to use any such improvements, modifications or alterations anywhere outside of China, Hong Kong, Macau and Taiwan.

In May 2020, the company and Genexine entered into an amendment to this agreement, whereby both parties desire to establish a collaboration on TJ107 GBM Study in Greater China. Under the terms of the expanded collaboration, the company will be mainly responsible for using commercially reasonable efforts to conduct the Phase 2 GBM clinical trial in Greater China, and Genexine will share the development strategies, data and costs for success of this clinical trial.

Licensing Agreement with Ferring (Olamkicept)

In November 2016, the company entered into a license and sublicense agreement with Ferring International Center SA ('Ferring') with respect to (i) FE301, an interleukin-6 inhibitor, and (ii) all pharmaceutical formulations in finished packaged form containing FE301 covered by certain patents or patent applications. Under this agreement, Ferring granted to the company an exclusive, sublicensable license (excluding any non-exclusive license that Ferring granted to Conaris Research Institute AG under a licensing agreement entered into in November 2008) under certain Ferring intellectual property to research, develop, make, have made, import, use, sell and offer to sell FE301 (and the licensed products containing FE301) in China, Hong Kong, Macau, Taiwan and South Korea. The company also has an option to receive an exclusive, sublicensable license under certain Ferring intellectual property to research, develop, make, have made, import, use, sell and offer to sell FE301 (and the licensed products containing FE301) in the countries in North America, the European Union and Japan that are mutually agreed upon by the parties.

The company is required to use commercially reasonable efforts to obtain approval of FE301 and to promote, market, distribute and sell it in China, Hong Kong, Macau, Taiwan, and South Korea.

In September 2020, the company entered into a sublicense agreement with I-Mab Hangzhou, under which the company sublicensed to I-Mab Hangzhou an exclusive, sublicensable license to develop, manufacture and commercialize olamkicept in mainland China, Hong Kong, Macau, Taiwan and South Korea. In December 2021, the company entered into a supplementary sublicensing agreement with I-Mab Hangzhou, pursuant to which I-Mab Hangzhou, as a sub-licensee of olamkicept (TJ301) in Greater China and Korea, agreed to pay to the company for the completion of olamkicept (TJ301) Phase 2a study report.

In May 2022, the company entered into an amended and restated license and sublicense agreement and a cell line and manufacturing collaboration agreement (the 'Cell Line Collaboration Agreement') with Ferring, under which the company granted to Ferring an exclusive, perpetual and transferrable sublicense, with the right to grant further sublicenses to sublicensees, under all of the intellectual properties licensed to the company by its business partner, to research, develop, make, import, use and sell olamkicept as expressed by or produced by cell lines created by the company's business partner and its affiliates in any human indications in the territories other than Greater China and Korea. The company also granted to Ferring an exclusive, perpetual and royalty-free license, with right of sublicense to sublicensees, under the intellectual property owned or controlled by the company's company which relates to cell lines created by the company's business partner and its affiliates, for the research, development, making, using or selling of olamkicept, including prespecified patents and know-how and improvements thereto.

License and Collaboration Agreement with MacroGenics (enoblituzumab)

In July 2019, the company entered into a license and collaboration agreement with MacroGenics, Inc. for the development and commercialization of an Fc-optimized antibody known as enoblituzumab that targets B7-H3, including in combination with other agents, such as the anti-PD-1 antibody known as retifanlimab (formerly MGA012), in the People's Republic of China, Hong Kong, Macau and Taiwan.

Under this agreement, MacroGenics granted to the company an exclusive, sublicensable, royalty-bearing license to MacroGenics' patents and know-how to develop and commercialize the enoblituzumab product, and a combination regimen of enoblituzumab and retifanlimab, in Greater China during the term of the agreement.

In exchange for these rights, in addition to certain financial consideration, the company grant to MacroGenics a royalty-free, sublicensable, license outside of Greater China, to the company's patents and know-how that are related to the enoblituzumab product or useful or necessary for MacroGenics to develop or commercialize the enoblituzumab product or a product containing retifanlimab, and combinations thereof. The license is (i) non-exclusive with respect to the enoblituzumab product, and (ii) exclusive with regard to retifanlimab.

The company exercised its right to terminate the license and collaboration agreement with MacroGenics by serving a termination notice on August 29, 2022 and the termination came into effect in February 2023.

Other In-Licensing Arrangements

In November 2018, the company entered into a license and collaboration agreement with MorphoSys for MorphoSys's proprietary antibody (MOR210/TJ210) directed against C5aR (the 'C5aR Agreement'). Under this agreement, MorphoSys granted to the company an exclusive, royalty-bearing license to explore, develop and commercialize MOR210/TJ210 in Greater China and South Korea and allowed the company to share certain economics upon certain clinical milestones in the U.S.

In the event of such termination, in addition to other obligations, the company must grant to MorphoSys an exclusive, royalty-bearing, sublicensable license under certain of the company's intellectual property relating to the licensed product to exploit MOR210/TJ210 in Greater China and South Korea.

Out-Licensing Arrangements

License and Collaboration Agreement with AbbVie

In September 2020, the company, through its subsidiaries I-Mab Biopharma Co., Ltd. and I-Mab Biopharma US Limited, entered into a license and collaboration agreement with AbbVie Ireland Unlimited Company ('AbbVie') for the development and commercialization of certain compounds and products that target CD47, including lemzoparlimab (which targets a unique epitope of CD47).

Under this agreement, the company grants AbbVie an exclusive, royalty-bearing, sublicensable license to develop, manufacture and commercialize the licensed compounds and products (but excluding products that are directed to both a CD47 epitope that is not the same or substantially similar to the epitope targeted by lemzoparlimab and a non-CD47 target) anywhere in the world outside of mainland China, Hong Kong and Macau; and to conduct development and manufacturing activities in mainland China, Hong Kong and Macau to further AbbVie's commercialization of the licensed products outside of mainland China, Hong Kong and Macau, except that, with respect to products containing either the company's preclinical CD47-PDL1 compound or the company's preclinical CD47-GMCSF compound, AbbVie will not develop, manufacture or commercialize such products until the parties come to financial terms on such products following AbbVie's exercise of its rights of first negotiation. The company has granted AbbVie a license and cannot commercialize products containing the company's preclinical CD47-PDL1 compound or the company's preclinical CD47-GMCSF compound outside of mainland China, Hong Kong and Macau even if AbbVie does not exercise its right of first negotiation or the company is unable to come to financial terms on such products. The company also grants AbbVie a co-exclusive, royalty-bearing, sublicensable license to develop, manufacture and commercialize licensed compounds and products that are directed to both a CD47 epitope that is not the same or substantially similar to the epitope targeted by lemzoparlimab and a non-CD47 target (excluding such compounds and products that have been developed by the company) anywhere in the world.

Under this agreement, AbbVie grants the company an exclusive, royalty-free, sublicensable license under its technology and any joint technology developed under this agreement to clinically develop and commercialize in mainland China, Hong Kong and Macau certain of the licensed compounds and products that (1) only target CD47, including lemzoparlimab, and (2) to the extent AbbVie exercises its rights of first negotiation for such licensed compounds and products, consist of the company's preclinical CD47-PDLl compound or the company's preclinical CD47-GMCSF compound.

The company is responsible for the development and commercialization of the licensed compounds and products in mainland China, Hong Kong and Macau. The company is required to use commercially reasonable efforts to develop, seek and obtain approval of, and commercialize at least one licensed product in at least two indications in mainland China.

In August 2022, the company and AbbVie Global Enterprises Ltd., the assignee of AbbVie Ireland Unlimited Company (together with AbbVie Ireland Unlimited Company, 'AbbVie'), entered into an amendment to this agreement. The parties are collaborating on the global development of anti-CD47 antibody therapy under the agreement as amended. The company has the exclusive right to develop and commercialize all licensed products under the agreement (as amended) in Greater China. AbbVie discontinued the global Phase 1b study of lemzoparlimab combination therapy with AZA and venetoclax, in patients with MDS and AML, and a Phase 1b study of lemzoparlimab in patients with relapsed/refractory multiple myeloma.

Licensing Agreement with ABL Bio

In July 2018, the company entered into a license and collaboration agreement with ABL Bio (the 'ABL Bio License'), as amended from time to time. Under the ABL Bio License, the company granted to ABL Bio exclusive, worldwide (excluding Greater China), royalty-bearing rights to develop and commercialize a bispecific antibody (the 'BsAb') using certain of the company's monoclonal antibody sequences. ABL Bio has developed expertise in the area of bispecific antibodies for all indications and has developed proprietary intellectual property around the BsAb technology, and the license allows ABL Bio to further develop and commercialize the BsAb based on monoclonal antibodies licensed from the company under the ABL Bio License. ABL Bio granted to the company an exclusive, royalty-free, sublicensable license under its interest in the BsAb and related know-how (including improvements thereto) to exploit the licensed BsAb in Greater China.

In addition, ABL Bio granted to the company an exclusive, royalty-free, sublicensable license to use its BsAb technology solely to exploit the licensed BsAb product for all indications in Greater China.

Licensing Agreement with CSPC Entity

In December 2018, the company entered into a product development agreement (the 'CSPC Agreement') with an entity controlled by CSPC Pharmaceutical Group Limited (HKEX: 1093) ('CSPC entity'). Under the CSPC Agreement, the company granted to CSPC entity exclusive, non-transferable, non-irrevocable and sublicensable rights under the company's patent rights in China to develop and commercialize TJ103 for treating type 2 diabetes mellitus and any other potential therapeutic applications.

Other Out-Licensing Arrangements

In April 2017, the company's subsidiary I-Mab Shanghai entered into a technology transfer agreement (the 'HDYM License') with Ningbo Hou De Yi Min Information Technology Co., Ltd. ('HDYM') and Hangzhou HealSun Biopharm Co., Ltd. ('HealSun') with respect to PD-L1 humanized monoclonal antibodies. Under the HDYM License, I-Mab Shanghai agreed to grant to HDYM exclusive (even to I-Mab Shanghai itself), worldwide and sublicensable rights to develop, manufacture, have manufactured, use, sell, have sold, import, or otherwise exploit certain PD-L1 related patents, patent applications, know-hows, data and information of I-Mab Shanghai, relevant cell lines, as well as any PD-L1 monoclonal antibody arising from such cell lines for the treatment of diseases. Further, I-Mab Shanghai and its cooperative party HealSun agreed to provide subsequent research and development services on such intellectual property to HDYM, including the selection and examination of innovative PD-L1 humanized monoclonal antibodies, cultivation and selection of stable cell lines, establishment of cell bank, research and development of manufacturing processes and preparation of samples, toxicological and pharmacological testing, pre-clinical pharmaceutical experiment report drafting, and application for and registration of clinical trials.

In March 2020, the company entered into a strategic partnership with Kalbe Genexine Biologics ('KG'), a joint venture of Kalbe Farma Tbk ('Kalbe') and Genexine. Under the terms of the agreement, KG will receive a right of first negotiation for an exclusive license for the commercialization of two I-Mab-discovered product candidates: uliledlimab, a differentiated anti-CD73 antibody in Phase 1 development for advanced solid tumors, and an I-Mab product candidate to be agreed upon by both parties. With the agreement, KG will have a right of first negotiation for exclusive rights to commercialize these two product candidates in the ASEAN (Brunei Darussalam, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand and Vietnam) and MENA (Algeria, Bahrain, Djibouti, Egypt, Israel, Jordan, Kuwait, Lebanon, Malta, Morocco, Oman, Qatar, Saudi Arabia, Tunisia, the United Arab Emirates, and Palestine) regions, as well as Sri Lanka.

Collaboration Arrangements

In July 2018, the company entered into a collaboration agreement with ABL Bio, further amended in November 2018, May 2019, December 2019, June 2020, September 2021, respectively, whereby both parties agreed to collaborate to develop two bispecific antibodies by using ABL Bio's proprietary BsAb technology and commercialize them in their respective territories, which, collectively, include Greater China and South Korea, and other territories throughout the rest of the world if both parties agree to do so in such other territories during the performance of the agreement.

In September 2018, the company entered into a collaboration and platform technology license agreement with WuXi Biologics Ireland Limited ('WuXi Biologics'), whereby both parties agreed to collaborate in the research and development of at least three bispecific antibodies for the company's company to commercialize them worldwide. Such bispecific antibodies will be created using the company's proprietary monoclonal antibodies and WuXi Biologics' proprietary WuXiBody platform technology for generating bispecific antibodies, will be developed and manufactured through the exclusive service of WuXi Biologics.

In April 2019, the company extended its existing partnership with WuXi Biologics (Shanghai) Co., Ltd. ('WuXi Biologics Shanghai'). The company entered into a long-term, strategic collaboration agreement with WuXi Biologics Shanghai to facilitate the CMC development and GMP manufacturing of both clinical and commercial supplies of certain of the company's monoclonal and bispecific antibodies and fusion products, leveraging WuXi Biologics' and its affiliates' expertise in this area and supporting the company's pre-existing collaboration and platform technology license agreement with WuXi Biologics.

In November 2018, the company entered into collaboration agreements with Tracon Pharmaceuticals, Inc. ('Tracon'), whereby the company and Tracon agreed to (i) co-develop the company's proprietary CD73 antibody, TJD5 (the 'TJD5 Agreement') and (ii) collaborate to co-develop up to five bispecific antibodies (the 'BsAbs Agreement').

In March 2021, the company entered into two collaboration agreements with Complix, an EU-based biotech company (the 'Complix Agreement'), and Affinity, a Shanghai-based biotech company (the 'Affinity Agreement'), respectively, allowing the company to access cutting-edge technology platforms to create next generation of novel and highly differentiated drug candidates, including Cell Penetrating Alphabodies ('CPAB') for otherwise intractable intracellular drug targets and masked antibodies for targeted tumor-site activation. Under the Complix Agreement, both parties will collaborate to discover, develop and commercialize novel therapeutics for mutually agreed targets based on Complix's proprietary technology. Under the Affinity Agreement, both parties will collaborate to develop lead compounds for mutually agreed targets based on Affinity's Tumor MicroEnvironment Activated body ('TMEAbody') platform technology.

In July 2021, the company entered into a collaboration agreement with Immorna, an mRNA biotech company, to discover and develop self-replicating mRNA for in vivo synthesized therapeutic biologics. In the same month, the company entered into a collaboration agreement with neoX Biotech, an AI-enabled R&D biotech company, to accelerate the R&D process of novel targets and modalities. In March 2023, the company terminated the collaboration agreement with Immorna.

In October 2021, the company entered into a strategic partnership with Sinopharm to strengthen the company's commercial capabilities and support the company's commercialization transformation. The company will authorize more than 300 of Sinopharm's subsidiaries as distributors across China to support distribution and retail allocation to terminal markets while the company lead the overall commercial activities. The partnership will also include alliance on key projects, to jointly support the commercialization and go-to-market process of the company's differentiated and novel products.

In November 2021, the company entered into a strategic collaboration agreement with Jumpcan, a leading China pharmaceutical company specialized in and committed to pediatric medicines, for the development, manufacturing and commercialization of the company's highly differentiated long-acting recombinant human growth hormone, eftansomatropin alfa (TJ101) in mainland China. Under the collaboration agreement, the company will continue to lead the ongoing registrational Phase 3 clinical trial of eftansomatropin alfa in pediatric growth hormone deficiency (PGHD).

In November 2021, the company also entered into a strategic collaboration with Roche Diagnostics, a global leader in in vitro diagnostics industry, to co-develop companion diagnostics (CDx) solutions for the company's innovative pipeline, at the Fourth China International Import Expo (CIIE) in Shanghai. Under this collaboration, the company and Roche Diagnostics will jointly develop companion diagnostics solutions for the innovative assets under development by the company to accelerate the research and development process of innovative biologics with cutting-edge diagnosis and treatment technologies.

Intellectual Property

As of December 31, 2022, the company's owned patent portfolio consisted of 113 issued patents, including 11 issued in the U.S., 16 issued in the PRC, seven issued in Korea and 79 issued in other jurisdictions; and 185 pending patent applications, including 19 PCT patent applications, 10 U.S. patent applications, 14 PRC patent applications and 142 patent applications in other jurisdictions. The company's owned patents and patent applications primarily relate to the drug candidates in the company's Global Portfolio. Furthermore, as of December 31, 2022, the company in-licensed the Greater China and Korea rights relating to 35 issued patents, including 14 issued in the PRC, three issued in Korea, 12 issued in Hong Kong, two issued in Macau and four issued in Taiwan; and 26 pending patent applications, including two PCT patent applications, 12 PRC patent applications, four Hong Kong patent applications, six Taiwan patent applications, one Korean patent applications and one Macau patent application. The in-licensed patents and patent applications primarily relate to felzartamab, eftansomatropin alfa, efineptakin alfa and TJ210.

Felzartamab

As of December 31, 2022, the company exclusively licensed from MorphoSys 18 issued patents (including eight issued in the PRC, seven issued in Hong Kong, one issued in Taiwan and two issued in Macau) and 13 pending patent applications (including four PCT applications, two in the PRC, two in Hong Kong, and five in Taiwan) relating to felzartamab. The licensed patents include composition of matter patents in China, Hong Kong, Taiwan and Macau. The patents (including patent applications if issued) in this portfolio are expected to expire between 2025 and 2042, before taking into account any extension that may be obtained through patent term extension or adjustment, or term reduction due to filing of terminal disclaimers.

Eftansomatropin alfa

As of December 31, 2022, the company exclusively licensed from Genexine two pending PRC patent applications and two PCT applications directly relating to eftansomatropin alfa; and non-exclusively licensed from Genexine 3 issued patents in the PRC relating to a hyFc platform that develops eftansomatropin alfa. The licensed patents include composition of matter patents in China. The patents (including patent applications if issued) in this portfolio are expected to expire between 2028 and 2037, before taking into account any extension that may be obtained through patent term extension or adjustment, or term reduction due to filing of terminal disclaimers.

Efineptakin alfa

As of December 31, 2022, the company exclusively licensed from Genexine three issued patents (including three issued in Taiwan) and eight pending patent applications (including seven in the PRC and one in Hong Kong) directly relating to efineptakin alfa; and non-exclusively license from Genexine five issued patents in the PRC and four issued patents in Hong Kong relating to a hyFc platform that develops efineptakin alfa. The patents (including patent applications if issued) in this portfolio are expected to expire between 2028 and 2040, before taking into account any extension that may be obtained through patent term extension or adjustment, or term reduction due to filing of terminal disclaimers.

Lemzoparlimab

As of December 31, 2022, the company owned eight PCT patent application, three of which has entered national phases, including in the PRC, the United States and additional jurisdictions. The company expects that any patents that may issue under these applications will expire between 2037 and 2042, before taking into account any extension that may be obtained through patent term extension or adjustment, or term reduction due to filing of terminal disclaimers.

Uliledlimab

As of December 31, 2022, the company owned four PCT patent applications and one of which has entered national phases including in the PRC, the United States, and additional jurisdictions. The company expects that any patent that may issue under these applications will expire between 2038 and 2042, before taking into account any extension that may be obtained through patent term extension or adjustment, or term reduction due to filing of terminal disclaimers.

TJ210

As of December 31, 2022, the company exclusively licensed from MorphoSys four pending patent applications (including one in the PRC, one in Hong Kong, one in Taiwan and one in Korea) relating to TJ210. The company co-owned one PCT application with MorphoSys relating to TJ210. The company expects that any patent that may issue under these applications will expire between 2040 and 2041, before taking into account any extension that may be obtained through patent term extension or adjustment, or term reduction due to filing of terminal disclaimers.

Givastomig (TJ-CD4B)

As of December 31, 2022, the company co-owned one PCT patent application with ABL Bio Inc., which has entered national phases including in the PRC, the United States, and additional jurisdictions. The company owned one PCT application relating to TJ-CD4B. The company expects that any patent that may issue under this application will expire between 2040 and 2042, before taking into account any extension that may be obtained through patent term extension or adjustment, or term reduction due to filing of terminal disclaimers.

TJ-L14B

As of December 31, 2022, the company co-owned one PCT patent application with ABL Bio Inc., which has entered national phases including in the PRC, the Europe, and additional jurisdictions. The company expects that any patent that may issue under this application will expire 2039, before taking into account any extension that may be obtained through patent term extension or adjustment, or term reduction due to filing of terminal disclaimers.

Additionally, as of December 31, 2022, the company had 17 registered trademarks in Hong Kong, 98 registered trademarks in the PRC, six registered trademarks in the United States, 17 registered trademarks in Macau, 16 registered trademarks in Taiwan, three registered trademarks in other jurisdictions, and four trademark applications in the PRC; 10 domain names in the PRC, including www.i-mabbiopharma.com, six domain names in Hong Kong and two domain names in the Cayman Islands; and 12 software copyrights and three copyrights of works of art in the PRC.

Regulation

In the United States, the FDA regulates the company's drug candidates as biological products, or biologics, under the Federal Food, Drug, and Cosmetic Act (the 'FDCA'), the Public Health Service Act and associated implementing regulations.

Manufacturing and Supply

The company outsources the manufacturing of clinical trial material for the company's internally developed, IND enabling projects to leading CDMOs in China such as WuXi Biologics.

Research and Development

The company incurred research and development expenses of RMB904.9 million (U.S.$131.2 million) for the year ended December 31, 2022.

History

I-Mab was founded in 2014. The company was incorporated in the Cayman Islands in 2016.

Country
Founded:
2014
IPO Date:
01/17/2020
ISIN Number:
I_US44975P1030

Contact Details

Address:
New Bund Center, 55th Floor, 555 West Haiyang Road, Pudong District, Shanghai 200124, China
Phone Number
86 21 6057 8000

Key Executives

CEO:
Kannan, Raj
CFO
Joseph, Skelton
COO:
Data Unavailable