Abstract 4080: IBB0979, A novel B7H3/IL-10 immunocytokine of monovalent anti-B7H3 antibody fused with IL-10 homodimer

Abstract

Abstract Background: This study demonstrates the preclinical evaluation of a novel B7H3/IL-10 immunocytokine IBB0979. IBB0979 was designed to solve the problems of immune cell exhaustion and drug resistance in current immunotherapy. As the tumors progress, the domination of progenitor exhausted T cells (which are the major target cells of current PD-1/L1 based immunotherapy) will be replaced by terminally exhausted T cells (which are the major target cells of IL-10) causing resistance of current PD-1/L1 based therapies. Thus, IL-10 is a potent activator of antigen-specific CD8+ T cells in the tumor microenvironment and can restore the tumor-killing activity of tumor-infiltrating lymphocytes by restoring the oxidative phosphorylation metabolism of terminally exhausted T cells. B7H3 is highly expressed on various tumors but expressed at lower levels in normal tissues and blood vessels, which makes it an ideal target for developing cancer treatment. Also, B7H3 antibody extended the half-life and performed tumor-targeted delivery of IL-10, which improves the safety and efficacy of IL-10. Methods: We designed several structures of B7H3 antibody and IL-10 bifunctional fusion protein. Binding activity to B7H3 and IL-10 receptor was evaluated by both ELISA and FACS. C57BL/6J mice bearing MC38-hB7H3 cell line were used to evaluate the anti-tumor efficacy of IBB0979. Preclinical PK and toxicity study was also performed in cynomolgus monkeys to describe the safety profile of IBB0979. Results: Preclinical study showed that IBB0979 has high affinity to both targets and exhibited potent TGI in C57BL/6J mice bearing MC38-hB7H3 cell line, with TGI of 100% at 0.3mg/kg, 1mg/kg and 3mg/kg. An in vivo study in cynomolgus monkeys showed that after intravenously administered with 1 mg/kg, 2 mg/kg and 6 mg/kg of IBB0979 once a week for 29 days (5 times in total, given on days 1, 8, 15, 22 and 29), MTD was not reached up to 6 mg/kg which is significantly higher than the 10-20 μg/kg tolerated by IL-10 cytokines alone. Conclusion: IBB0979 is the world's first B7H3/IL-10 immunocytokine receiving IND approvals from both the FDA and the NMPA, showing excellent preclinical efficacy and safety profile. The Phase I clinical trial is currently on-going, with the first patient dosed in July 2023 and achieved SD at first efficacy evaluation after 2 cycles of administration. Since B7H3 is overexpressed in a wide range of cancers including lung, prostate, glioma, thyroid, head and neck, rectal, breast, skin, renal cell, and ovarian cancers, IBB0979 has the potential to become a next-generation therapy for resolving T cell exhaustion in cancer patients. Citation Format: Xiaoling Jiang, Chongbing Wu, Zi Chen, Liusong Yin. IBB0979, A novel B7H3/IL-10 immunocytokine of monovalent anti-B7H3 antibody fused with IL-10 homodimer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4080.