I-Mab and ABL Bio Inc. jointly announced preclinical data of their 4-1BB bispecific antibodies at the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting. The new data demonstrate the unique mechanisms of action of TJ-CD4B/ABL111 and TJ-L14B/ABL503 which have resulted in localized drug action and reduced systemic toxicity, as well as sustained anti-tumor efficacy. Stimulation of 4-1BB is a promising therapeutic strategy for improving the current immunotherapy for multiple cancers.

TJ-CD4B/ABL111 and TJ-L14B/ABL503, both jointly developed by I-Mab and ABL, are undergoing phase 1 clinical studies in the United States. TJ-CD4B/ABL111 Poster title (#702): TJ-CD4B (ABL111), a Claudin18.2-targeted 4-1BB tumor engager induces potent tumor-dependent immune response without dose-limiting toxicity in preclinical studies The preclinical studies confirmed the unique pharmacodynamic data and safety of TJ-CD4B/ABL111 in animal models and cell cultures. Analysis of the data found: Potent, anti-tumor activity was observed with the proliferation of immune cells in the tumor microenvironment (TME) as well as an increase in memory T cells in the peripheral blood, suggesting long-term immunity against the tumor.

TJ-CD4B/ABL111 was well tolerated in non-human primates and did not induce a systemic immune response or liver toxicity up to levels of 100mg/kg. Activation of immune pathways by TJ-CD4B/ABL111 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. Poster title (#892): ABL503 (TJ-L14B), PD-L1x4-1BB bispecific antibody induces superior anti-tumor activity by PD-L1-dependent 4-1BB activation with the increase of 4-1BB+CD8+ T cells in tumor microenvironment The preclinical study data confirms the unique mechanism of action of TJ-L14B/ABL503 and its potential to treat resistance to PD-L1 therapies.

Analysis of the data found: PD-L1-dependent stimulation of the 4-1BB signaling pathway was demonstrated in 4-1BB bioassays with PD-L1 expressing tumor cells. More potent 4-1BB activation by TJ-L14B/ABL503 was observed at higher PD-L1 expression confirming the requirement of PD-L1 on both tumor and immune cells for optimal activity. Cytokine release assays have also demonstrated minimal peripheral toxicity with TJ-L14B/ABL503.

The in vivo efficacy of TJ-L14B/ABL503 was demonstrated in animal models with tumors expressing different levels of PD-L1. TJ-L14B/ABL503 showed anti-tumor efficacy across the PD-L1 levels. In particular, TJ-L14B/ABL503 demonstrated superior anti-tumor efficacy than atezolizumab in tumors with low PD-L1 expression.

In vitro tumor-killing activity of TJ-L14B/ABL503 was superior compared to atezolizumab when tested in organoid system, even in organoids from atezolizumab non-responders. Pharmacodynamic changes in TILs and blood were evaluated in animal models. An increase in 4-1BB+ cells, CD8+ T cells, and effector memory T cells was observed in the TME and blood, indicating a strong and long-lasting anti-tumor immune response.

Treatment with TJ-L14B/ABL503 increased MIG/CXCL9, MIP-1b/CCL4, and s4-1BB in the serum, and can potentially be used as pharmacodynamic markers in clinical trials. TJ-CD4B, also known as ABL111, is a Claudin 18.2 and 4-1BB bispecific antibody capable of binding to tumor cells expressing Claudin 18.2, i.e., gastric cancer and pancreatic cancer cells, and stimulating intra-tumoral T cells by the 4-1BB arm designed to be activated only upon tumor engagement while silent elsewhere. TJ-CD4B/ABL111 effectively maintains a strong tumor binding property and anti-tumor activity attributable to a synergistic effect of both Claudin 18.2 antibody and 4-1BB antibody while it avoids or minimizes liver toxicity and systemic immunotoxicity commonly seen with 4-1BB antibodies as a drug class.

Being developed under collaboration between I-Mab and ABL, TJ-CD4B/ABL111 is currently being investigated in a phase 1 clinical study in the U.S. Being developed jointly with ABL, TJ-L14B/ABL503 is a differentiated PD-L1-based bispecific antibody with the PD-L1 arm as the tumor-dependent T-cell activator and the 4-1BB arm as the conditional T cell activator upon tumor engagement. Using ABL's “Grabody-T” bispecific antibody platform technology, TJ-L14B/ABL503 stimulates 4-1BB activation only in the presence of PD-L1 expressing tumor cells to minimize the risk of off-tumor toxicity. Preclinical studies have demonstrated that the bispecific antibody shows better anti-tumor activity than equimolar doses of single agents alone or in combination.

Phase 1 study in currently being conducted in the U.S.