Our innovative discovery engine is built around the world-class expertise of a group of seasoned immunologists with extensive academic research and drug R&D experience. Our discovery team possesses world-class expertise in cutting-edge target biology and immunology to identify, create and translate science into “points of innovation” or differentiation to develop novel molecules. In a short span of four years, we have generated a panel of novel or highly differentiated drug molecules. Three of our monoclonal antibodies have entered clinical studies in the US and China.
Target Biology to Create Novel or Highly Differentiated Molecules
Our world-class expertise in immunology drives the identification of biological targets, and their immunological mechanisms of action, across the two therapeutic areas we focus on. Our discovery team has deep expertise in functional assays across a wide range of immune cells, including T cells, B cells and macrophages. By designing robust, high-throughput assays, we significantly increase screening efficiency and the probability of finding differentiated molecules.
Our discovery team is passionate about, and has excelled in, developing novel monoclonal antibodies by creating clinically meaningful differentiated, as well as novel or highly differentiated, bi-functional molecules that synergize biologic properties. For example, the demonstrated differentiation of TJC4 and TJD5 was engineered by design from an antibody screen through stepwise in vitro and in vivo validation processes.
Instead of performing routine or traditional antibody screening, we set a specific goal to identify and select a unique CD47 antibody that is free from binding to red blood cells (RBC) among all CD47 antibody leads that naturally bind to RBCs. As a result, we selected, by design, our proprietary CD47 antibody (TJC4), with a rare epitope, uniquely spares binding to RBCs, which differentiates it from other CD47 antibodies that typically cause hematologic side effects. TJC4 has been validated in a series of in vitro assays as well as multiple monkey studies for its unique differentiation and is in a Phase 1 clinical trial in the US.
Another example of our R&D capability relates to our novel bi-specific antibody panel that represents a new wave of oncology drug candidates. We have created novel bi-specific antibodies with novel biological properties that are capable of enriching immune cells in tumors through dual targeting of PD-L1 and activating immune cells for a synergistic anti-tumor effect. These bi-specific drug candidates have been shown to exhibit unique properties that render tumors more responsive to treatment. TJ-C4GM and TJ-L1I7, for example, were designed as bi-functional molecules to specifically treat solid tumors that otherwise may not respond to the CD47 antibody alone, or tumors that respond poorly to standard PD-1 and PD-L1 treatment, respectively.
This discovery expertise, combined with our ‘fit-for-purpose’ antibody-engineering technology platforms as described below, fuels a powerful engine of innovation to create novel or highly differentiated molecules.
Fit-for-Purpose Technology to Create Novel Molecules
We utilize four antibody or molecular engineering platforms in our ‘fit-for-purpose toolbox’ to engineer drug molecules that capture defined biologic properties of bi-specific antibodies and retain good manufacturability and druggability of the molecules. To date, we have created seven novel preclinical stage bi-specific drug molecules.
In addition to our own Ig-scFv bi-specific antibody platform, we have partnered with ABL Bio and WuXi Biologics to access their antibody engineering platforms in order to increase the probability of success, as different molecular configurations require different technologies. Furthermore, our proprietary antibody-cytokine technology has enabled another form of bi-specific antibodies, such as TJ-L1I7 and TJ-C4GM, that link a tumor-engaging antibody with an immuno-modulatory cytokine.
Tumor cells overexpress CD47 which engages signal-regulatory protein (SIRPa) on macrophages (mf) to deliver a “do-not-eat” signal to avoid being phagocytosed.
I-Mab has developed a novel CD47 antibody, TJC4 also known as TJ011133, which was endowed with an RBC sparing property and unique binding epitope, may have better safety profile based on the pre-clinical data.
CD47 blockade using SIRPα-Fc or anti-CD47 antibodies results in inhibition of the ‘do not eat’ signal and activation of phagocytosis and has emerged as a promising cancer treatment strategy. However, targeting CD47 leads to various hematological toxicities, particularly anemia and thrombocytopenia. Lemzoparlimab (also known as TJ011133 or TJC4) is a fully human, anti-CD47 IgG4 antibody that is endowed with a red blood cell (RBC) sparing property and unique binding epitope, potentially differentiating itself from other CD47 axis targeting therapies.
LAG3 is a negative regulator of T cells. Persistent T-cell activation in a chronic inflammatory environment, as in a tumor or during chronic viral infection, results in sustained LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production.
The immune checkpoint co-inhibitory receptor TIGIT (T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif) is expressed on activated CD4+ T, CD8+ T and NK cells and on regulatory T cells (Tregs). Blocking TIGIT interaction with its ligand CD155 can re-energize tumor antigen-specific CD8+ T cells, unleash NK cells and inhibit Treg-mediated immunosuppression in the tumor microenvironment.
CD47 blockade has emerged as a promising cancer immunotherapy by promoting phagocytosis of tumor cells. However, this treatment strategy may be limited by the predominant accumulation of macrophages with pro-tumor M2 phenotype.
Lymphocyte counts in the peripheral immune system and tumor are correlated with positive clinical outcomes in PD-(L)1 immunotherapy. Interleukin7 (IL7) is an immune homeostasis cytokine for T cells.
TJ107, an immuno-oncology agent also known as Hyleukin, is a T cell amplifier comprising a homodimer of engineered human interleukin-7 (IL-7) fused with Genexine’s proprietary long-acting platform hybrid Fc. IL-7 is a critical homeostatic factor for T cells, acting on T cells to increase their number, diversity and functionality.
Claudin 18.2 (CLDN18.2) is a gastric-specific membrane protein, and is believed to be an ideal tumor antigen for immunotherapy. I-Mab and ABL Bio co-develop a bispecific antibody CLDN18.2-4-1BB (TJCD4B). TJCD4B showed strong tumor growth inhibition (TGI) of CLDN18.2 expressing tumor cells, with an increase of tumor infiltrating lymphocytes. Our data suggested TJCD4B activated 4-1BB in a CLDN18.2-dependent manner, thus addressing the safety concern associated with 4-1BB-based therapies. TJCD4B is a promising IO therapeutic option for gastric and other CLDN18.2-positive tumors.
We seek to strengthen our intellectual property (IP) portfolio continuously through in-house R&D and in-licensing. To maintain our competitive advantage, we strive to safeguard our proprietary technology and drug candidates. With the help of our US and China IP counsels, we are establishing an efficient IP management system for patent filing, portfolio management, and confidentiality management.
As of December 31,2020, our patent portfolio consists of more than 270 issued patents and patent applications primarily related to the drug candidates in our Global Portfolio, e.g. TJC4, TJD5, TJX7, TJ-CD4B and so on. Meanwhile, we have in-licensed the Greater China rights of more than 50 issued patents and patent applications primarily involving TJ202, TJ101, TJ301, TJ271 (Enoblituzumab) and TJ107.