Abstract 1873: D3L-001, a novel bispecific antibody targeting HER2 and CD47, demonstrates potent preclinical efficacy in solid tumors

Abstract

Abstract Background: HER2 is overexpressed in different solid tumors, including 10-20% breast and gastric cancers. Many HER2-targeted drugs, including trastuzumab, pertuzumab, lapatinib, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd), have been approved for treatment of HER2-positive early and metastatic breast cancer (BC). However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant clinical improvements in patients with HER2-positive gastric cancer (GC), suggesting differences in HER2 mediated disease biology between HER2-positive BC and GC. Recent studies have suggested efficacy of HER2 antibodies could be further enhanced by antibody-dependent cellular phagocytosis (ADCP) principally regulated by “don’t-eat-me” CD47 signals, which is overexpressed in many HER2-positive cancers and suppresses phagocytosis through binding to SIRPα. Methods: BC and GC cell lines were used. Monocytes were isolated from human PBMC and differentiated into macrophages, which were used for in vitro ADCP assays. In in vivo animal experiments, D3L-001 and comparator antibodies were examined for efficacy in solid tumor xenograft models. Results: D3L-001 was designed to have higher HER2 affinity (KD < 1 nM) than that of CD47 (KD >10 nM). With this unique design, D3L-001 showed preferential binding to HER2/CD47 double positive tumor cells as compared to CD47 single positive cells. D3L-001 showed better anti-tumor effect than trastuzumab in a panel of solid tumor models, including but not limited to BC and GC cell lines or patient derived xenografts. Immunohistochemistry (IHC) analysis was performed in tumor FFPE slides to evaluate expression of HER2 and CD47 in the efficacy tested models, and we observed that D3L-001 showed broad tumor growth inhibition in HER2 or CD47 high/low expression models. In both in vitro and in vivo studies using breast cancer HCC1954, JIMT-1 and gastric cancer N87 models, we observed a synergistic effect in the combination of Trastuzumab with Magrolimab. Moreover, D3L-001 showed a trend of better efficacy than the combination of Trastuzumab and Magrolimab. These results confirm the synergistic effect of dual-targeting HER2 and CD47 simultaneously and suggest advantage of using bispecific antibodies to confer such effect. D3L-001 also displayed potent and comparable in vivo efficacy as Enhertu in gastric N87 model, and it showed synergistic in vivo efficacy, when combining with Pertuzumab or Paclitaxel, in breast HCC1954, JIMT-1 and gastric cancer N87 models. Conclusion: D3L-001, a novel HER2×CD47 bsAb, demonstrated potent anti-tumor effect in a variety of solid tumor models via HER2 guided CD47 co-blocking. It also showed synergistic efficacy when combining with other anti-tumor agents. D3L-001 will be further evaluated in clinic for its potential as a novel treatment option in HER2-positive BC, GC and other solid tumors. Citation Format: Haopeng Rui, Xiaofeng Yang, Jiahao Chen, Jia Wang, Zhiqiang Zheng, Zhiqiang Chen, Jingtao Lu, Peggy Wu, Janet Chen, Allison Wang, George Chen. D3L-001, a novel bispecific antibody targeting HER2 and CD47, demonstrates potent preclinical efficacy in solid tumors [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 1873.