多体药物偶联物（MDC）BD200 通过一种新型双靶向模式介导抗肿瘤活性

Purpose: The therapeutic efficacy of antibody drug conjugates (ADCs) relies on effective tumor targeting. However, intra-tumor and inter-lesional heterogeneity of target expression limit ADC efficacy. Moreover, treatment with an ADC exerts selective pressure favoring antigen-negative clones, thus enhancing drug resistance. To address this challenge, we introduce the Multibody technology, which allows for specific recognition of multiple tumor associated antigens through a simple symmetrical antibody. Methods: Multibodies maintain the format of natural, symmetrical IgGs but can adjust their binding to different tumor surface-enriched antigens. This multi-specificity is designed to improve drug efficacy, reduce resistance and widen the responding patient population. BD200 is a multibody drug conjugate (MDC) whose fragment variable (Fv) domain is designed to bind alternatively to either TROP2 or Nectin-4 with high specificity. In its symmetrical human IgG1 format, two such identical Fv domains create an “OR" gate enabling the MDCs to bind bivalently to cells that express target A, cells that express target B or cells that express both A and B. BD200 incorporates a topoisomerase 1 inhibitor-based linker-payload. We tested BD200's internalization and cell-killing on a wide array of tumor types, each expressing one or both antigens. In a series of in-vivo mouse studies using human cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models, we compared BD200's efficacy to that of several approved anti-TROP-2 and anti-Nectin-4 ADCs. In these studies, we also tested BD200 in tumors that are refractory to approved ADCs. Finally, we assessed PK in NHPs to cross-compare with data from approved ADCs. Results: BD200 demonstrated rapid internalization and strong cytotoxic potency across a wide range of tumor cells. While each approved monospecific ADC performed well on some tumor cell lines, BD200 was comparable or superior to approved ADC comparators with all cell lines tested in vitro. Assessing in vivo anti-tumor efficacy, BD200 showed deep and durable anti-tumor responses including in models refractory to approved ADCs. BD200 showed similar or superior serum stability and PK properties compared to approved ADCs. Conclusion: The preclinical data suggest that a bivalent MDC addresses the challenge of tumor heterogeneity, while retaining the developability and the functional traits of a natural, simple, symmetrical human IgG. This may allow BD200 to drive deeper responses in more tumor types and more patients than existing ADCs.