Abstract 2931: Functional characterization of KJ-103, a novel therapeutic anti-TROP2 heavy chain-only antibody

Abstract

Abstract Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein expressed during development and at lower levels in normal adult tissues. In many solid tumors TROP2 upregulation is associated with increased tumor aggressiveness, metastasis, and decreased survival in difficult-to-treat cancers, making it an attractive target for cancer therapy. TROP2 ADCs have been developed and one has been approved in breast cancer and advanced bladder cancer. The toxicity associated with the toxin payload and the development of resistance to the payload limits their use. We previously described an anti-TROP2 heavy chain-only antibody (HCAb), KJ-103. KJ-103 has demonstrated high potency in in vivo preclinical human models, including breast cancer, colon cancer, esophageal carcinoma and pancreatic cancer. In vivo efficacy of KJ-103 was strongly diminished by use of a IgG4-FALA variant which has negligible interaction with Fc gamma receptors indicating that effector function is the primary mechanism of action. Activity in mouse strains with deficiency in different immune cell types showed that macrophages were the predominant effector cell responsible for in vivo activity. Analysis of the xenograft microenvironment from different cancer models established a clear correlation between the in vivo efficacy and the degree of macrophage infiltration that was independent of the CD47 IHC score. In vitro, KJ-103 induces the phagocytosis by human macrophages of M0, M1 and M2 subtypes. KJ-103 also induced phagocytosis by mouse macrophages, that reflected human CD47 (huCD47)/mouse SIRPα (mSIRPα) affinity. Importantly, in vivo tumor regression was observed in NCG mouse models where there is nM huCD47/mSIRPα alpha affinity. In vivo dose response in SCID and NCG mice which have different huCD47/mSIRPα affinity showed tumor regression at doses levels of 2-10mg/kg in both strains. The huCD47/mSIRPα affinity effect was only obvious at low dose levels (0.5mg/kg). In a dose range finding study in cynomolgus monkeys KJ-103 was very well tolerated with no abnormal observations in clinical parameters and blood clinical chemistry and hematology. KJ-103 has been humanized and has the same degree of activity as the parental antibody. Immunohistochemistry showed that the KJ-103 epitope was expressed across many tumor types, including breast, colon, ovarian, and head and neck among others. KJ-103 is a HCAB that has demonstrated high levels of preclinical potency and safety making it suitable for clinical development for TROP2 positive tumors. Citation Format: Shugang Yao, Hiba Zahreddine, Amit Subedi, Liying Gong, Amogh Nair, Alex Zhou, Tiffany Cheng, Elijus Undzys, Dominic Hou, Lucy Lai, Luis A. Da Cruz, David Young. Functional characterization of KJ-103, a novel therapeutic anti-TROP2 heavy chain-only antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2931.