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• W4308382419 abstract "<h3>Background</h3> HER2 is overexpressed in different solid tumors, including 15-20% of breast cancer. The advent of HER2-targeted drugs, including antibodies (Ab), TKI and ADC, have revolutionized HER2+ cancer treatment; however, the disease will eventually recur in most patients. Recent studies have suggested efficacy of HER2 target antibodies (Ab) therapy could be further enhanced by antibody-dependent cellular phagocytosis (ADCP) principally regulated by antiphagocytic “don’t-eat-me” CD47 signals. CD47 is overexpressed in many HER2+ cancers, which suppresses phagocytosis through binding to SIRPα. In this study, an internally discovered anti-HER2×CD47 bispecific antibody (bsAb), D3L-001, demonstrated synergistic anti-tumor effect by HER2 guided CD47 co-blocking. It enhances macrophage mediated phagocytosis and significantly suppresses <i>in vivo</i> tumor growth while sparing hematological toxicities, which are typically induced by anti-CD47 antibodies. <h3>Methods</h3> SK-BR-3, HCC1954 and Jurkat cells were used. Cellular binding and <i>in vitro</i> blocking of CD47 and SIRPα interaction by Abs were measured by FACS. Monocytes were isolated from PBMC and differentiated into macrophages, which were then used for ADCP assays. Abs <i>in vivo</i> efficacy were examined in HER2+ tumor models. <h3>Results</h3> D3L-001 was designed to have higher HER2 affinity (K_D < 1 nM) than that of CD47 (K_D >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 (figure 1). This preferential binding prevents D3L-001 from inducing red blood cell hemagglutination <i>in vitro</i>. Moreover, its binding to HER2+ tumor cells wasn’t affected by whole blood cell pre-culture treatment, indicating low systemic CD47 antigen sink effect. Intriguingly, we found that D3L-001 can block the interaction between SIRPα and CD47 on HER2+ tumor cells very effectively, probably due to the avidity effect induced by the addition of HER2 binding arm (figure 2). This potent blocking translated well into enhanced <i>in vitro</i> phagocytosis ability. D3L-001 showed stronger anti-tumor effect than trastuzumab in a panel of HER2+ tumor models. We observed significant tumor growth inhibition and regression in trastuzumab resistant xenograft models in a dose-dependent manner. D3L-001 demonstrated better efficacy than combination of trastuzumab and magrolimab, indicating synergistic effect of co-blocking HER2 and CD47 in bispecific form. In addition, the combination of D3L-001 with pertuzumab also showed synergistic <i>in vivo</i> efficacy. <h3>Conclusions</h3> D3L-001 is a novel HER2×CD47 bsAb which demonstrated potent and synergistic anti-tumor effect via HER2 guided CD47 co-blocking in both <i>in vitro</i> and <i>in vivo</i> models. D3L-001 might provide a novel treatment approach for HER2+ cancers and overcome their resistance to current therapies." @default.
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• W4308382419 date "2022-11-01" @default.
• W4308382419 modified "2023-09-27" @default.
• W4308382419 title "1377 Preclinical characterization of D3L-001, a novel bispecific antibody that enhance phagocytosis and eradication of HER2 positive solid tumor via HER2 and CD47 dual blockade" @default.
• W4308382419 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1377" @default.
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