Abstract 6280: Preclinical development of a bispecific antibody-trap selectively targeting CD47 and HER2 for the treatment of breast as well as gastric cancer

Abstract

Trastuzumab executes anti-tumor efficacy mainly via antibody-dependent cell cytotoxicity (ADCC). However due to the fact that majority of the populations including patients with cancers carry a CD16A-158F allele which has low binding affinity to the Fc fragment of trastuzumab, response to trastuzumab treatment is hindered. Furthermore, overexpression of CD47 on cancer cells prevent macrophages from activation via Fc-FcγRIIa interaction due to the so called “Don’t eat me” signal. We therefore designed a bispecific mAb-trap designated as IMM2902. Extensive in vitro as well as in vivo characterization demonstrated that IMM2902 binds to both CD47 and HER2 with high affinity (KD = 5.8x10-10M for HER2; KD = 8.9x10-9M for CD47) and has stronger ADCC activity against NCI-N87 (EC50 = 0.054nM for IMM2902, v.s. 0.868nM for trastuzumab). In vivo efficacy studies in several xenograft tumor models revealed a robust anti-tumor activity as reflected by the complete elimination of established tumors in BT-474 breast cancer and NCI-N87 gastric xenograft models even at the dose as low as 3.5mg/kg. Interestingly, even in Herceptin-resistant breast tumor model, when administered at a dose of 10mg/kg, the established HCC-1954 tumors were also eliminated. Immunohistochemistry staining of the tumor tissues demonstrated an accelerated HER2 degradation which is highly correlated with tumor volume. IMM2902 has no impact on hemagglutination, nor does it have significant hemotoxicity following single as well as multiple administrations in non-human primate animals at different dosage. Our study suggests that IMM2902 has the potential to be an alternative promising treatment option for patients with her2-positive cancers refractory to trastuzumab treatment. Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang. Preclinical development of a bispecific antibody-trap selectively targeting CD47 and HER2 for the treatment of breast as well as gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6280.

Targeting macrophages: a novel treatment strategy in solid tumors

“…IMM2902 allows the drug to bind preferentially to tumor cells through the high-affinity activity of HER2, and it simultaneously exhibits the characteristics of not binding to human erythrocytes and avoiding “antigenic sink,” thus greatly enhancing the specific synergistic effect of the dual target on tumors. In nonhuman primates, different doses of IMM2902 had no effect on hemagglutination and no significant hematotoxicity [ 157 ]. The established BT-474 breast cancer and NCI-N87 gastric xenograft tumor models exhibited complete tumor elimination in in-vivo efficacy studies, even at doses as low as 3.5 mg/kg.…”

“…The established BT-474 breast cancer and NCI-N87 gastric xenograft tumor models exhibited complete tumor elimination in in-vivo efficacy studies, even at doses as low as 3.5 mg/kg. Significantly, in a Herceptin-resistant breast tumor model, HCC-1954 tumors, IMM2902 also yielded strong anti-tumor activity at a dose of 10 mg/kg [ 157 ]. IMM2902 has been approved to enter clinical trials for the primary indication of HER2-positive breast, gastric, lung, and other advanced solid tumors to assess its efficacy and safety in HER2 + advanced solid tumors (NCT05076591).…”