The CD47-targeting antibody ZL-1201 enhances anti-tumor activity of standard of care therapeutic antibodies by promoting phagocytosis in hematologic and solid tumor models

Abstract Therapeutic monoclonal antibodies (mAbs) comprise the standard of care (SoC) for several hematologic and solid cancer indications. These include rituximab for CD20-expressing lymphomas, trastuzumab for HER2-amplified cancers, and cetuximab for EGFR-driven solid tumors. Although the primary mechanism of action for these therapies is tumor-cell targeting, they are rarely curative, partly because tumor cells employ a variety of mechanisms to evade immune surveillance and blunt anti-tumor immune response. CD47 is upregulated in solid tumors and hematological malignancies and provides a critical anti-phagocytic signal to escape destruction by the innate immune system. Thus, CD47 may represent a promising therapeutic target for activating innate and adaptive immunity and enhancing the therapeutic potential of SoC antibodies in the clinic. Here we present preclinical data supporting the combinatorial effects of the CD47-targeting monoclonal antibody ZL-1201 with SoC mAbs in hematologic and solid tumor models. ZL-1201 potently blocked CD47/SIRPα interaction and enhanced phagocytosis as measured by flow cytometry and high-content imaging analysis. Notably, in combination with trastuzumab, cetuximab, and rituximab, ZL-1201 demonstrated enhanced phagocytosis across hematologic and solid tumor models expressing varying levels of CD47 in in vitro co-culture systems. Neutralizing the Fc receptor function of these SoC mAbs by blocking CD16, CD32, and CD64 abrogated the combinatorial effects, indicating that the CD47 blockade sensitized tumors to pro-phagocytic signals provided by ADCP-inducing mAbs in an Fc receptor-dependent manner. Treatment of xenografts with ZL-1201 also drove tumor-specific immune responses and remodeling of the tumor microenvironment, including increased activation of antigen-presenting cells, decreased frequencies of MDSC, and reduced expression of immune checkpoints such as PD-L1. Further, ZL-1201 in combination with trastuzumab, rituximab, or cetuximab significantly delayed tumor growth and increased survival in in vivo xenograft models, highlighting the pivotal role for CD47 as a resistance mechanism to these therapeutic mAbs and the opportunity to overcome resistance with ZL-1201 combination. In conclusion, ZL-1201 enhances the anti-tumor activity of SoC antibodies and augments the immunologic response by overcoming the CD47/SIRPα “don’t-eat-me” myeloid checkpoint. This study indicates that ZL-1201 may combine with a broad range of SoC mAbs to enhance their clinical benefit across a variety of hematologic and solid tumor indications. ZL-1201 is under Ph1 clinical investigation (NCT04257617). Citation Format: Anthony Cao, Jiaqing Yi, Renyi Wu, Christopher Szeto, Quiping Ye, Bing Wan, Karl Hsu, Omar Kabbarah, Haiying Zhou. The CD47-targeting antibody ZL-1201 enhances anti-tumor activity of standard of care therapeutic antibodies by promoting phagocytosis in hematologic and solid tumor models [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 3425.