Impact of IBI3017, an innovative bispecific anti-Trop2 and B7H3 antibody-drug conjugate, on anti-tumor efficacy in a wide range of tumors.

Abstract

e20508 Background: Bispecific ADCs (bsADCs) are positioned as an emerging, next-generation, class of therapeutics, combining the dual-targeting capabilities of bispecific antibodies (bsAbs) with the potent cytotoxicity of antibody-drug conjugates (ADCs). Trophoblast cell surface antigen 2 (Trop2) and B7 homolog 3 (B7H3) are tumor-associated antigens that are highly co-expressed in a variety of tumors, e.g., non-small cell lung cancer (NSCLC), prostate adenocarcinoma (PRAD) and breast cancer (BC), among others. IBI3017 is a novel first-in-class bispecific antibody-drug conjugate targeting Trop2 and B7H3. It is composed of an anti-Trop2/B7H3 bispecific antibody conjugated to a novel topoisomerase I inhibitor, NT1, with a drug-to-antibody homogeneity ratio of 8 (DAR8). Since Trop2 ADCs have shown on-target/off-tumor toxicity such as stomatitis and mucositis in clinical studies, we designed IBI3017 to have a reduced binding affinity to Trop2, making it weaker than its binding affinity to B7H3. This enhances the selectivity for Trop2-B7H3 co-expressing tumors while minimizing toxicity to normal tissues. Methods: The pharmacologic profiles of IBI3017 were assessed in vitro and in vivo including efficacy, pharmacokinetics and safety in Trop2 and B7H3 positive cell lines, cell-derived xenograft (CDX) models and cynomolgus monkeys. Results: IBI3017 demonstrated comparable or better cytotoxicity to parental Trop2 and B7H3 ADCs in cancer cell lines across various tumor types. In addition, IBI3017 showed superior in vitro bystander effect compared to Trop2 and B7H3 ADCs. In vivo efficacy was evaluated in various CDX models with different Trop2 and B7H3 expression levels. IBI3017 exhibited superior antitumor activity to Trop2 and B7H3 ADCs. IBI3017 displayed good safety profile in monkey GLP toxicology study (HNSTD = 25 mg/kg). Conclusions: In summary, IBI3017 demonstrates promising potential for delivering potent and broad anti-tumor activity across a range of solid tumors, offering broad clinical application opportunities.