Abstract 7270: Novel humanized cell and murine models expressing tumor-associated antigens for ADC toxicity and IO combination evaluation

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Abstract Introduction: Antibody-drug conjugates (ADCs) represent a breakthrough therapeutic class that provides tumor-targeted cytotoxicity while stimulating immune responses, offering promising potential when combined with immunotherapies and particularly with PD-1 inhibitors. Traditional xenograft tumor models developed in immunodeficient mice are employed to evaluate ADCs' anti-tumor efficacy. However, these models lack competent immune systems and human antigen expression in normal tissues, limiting their capacity to assess immune responses and toxicity. To address these limitations, we developed HuCell, mouse tumor cells engineered to express tumor associated antigen (hTAA) such as HER2, and HuGEMM, humanized for a specific drug target within mice with a functional immune system. In this study HuCell/HuGEMM humanized mouse models were developed to evaluate the efficacy of ADCs in combination with anti-PD-1 immunotherapy and toxicity. Methods: Surface expression of human HER2, Trop2, and Nectin-4 on MC-38 HuCell was verified using flow cytometry before and after inoculation on mice. 5×106 HuCells were subcutaneously inoculated into hHER2, hTrop2, hNectin4 and hHER2/hPD-1 models in C57BL/6 background or wild-type (WT) models. Tumor-bearing models were treated with monotherapy of trastuzumab-deruxtecan (T-Dxd), sacituzumab govitecan or enfortumab vedotin, or combination therapy with anti-PD-1 antibodies. For the toxicity study, 180 mg/kg T-Dxd and 100 mg/kg trastuzumab-emtansine (T-DM1) were injected into hHER2 mice weekly for two doses by intravenous injection. Results: A highly HER2-expressing HuCell line (clone #2) successfully grew in hHER2 models but not in WT models, with tumors displaying nearly 100% of human Her2 positive cells with high surface expression (2×105 molecules per cell). In dose response study, T-Dxd significantly inhibited tumor growth at 5 mg/kg and 10 mg/kg in C57BL/6-hHER2. Combination treatment of T-Dxd (4 mg/kg+2 mg/kg, QW) with Keytruda (5 mg/kg, BIW×2) resulted in a complete response rate (8/8) with 87% TGI (p<0.01) compared to T-Dxd monotherapy (7/8) with 96% TGI (p<0.001) in hHER2/PD-1 double knock in mice. In a toxicity study, T-DM1 showed liver toxicity, whereas T-Dxd did not. Both T-DM1 and T-Dxd exhibited notable hematological toxicity, consistent with clinical observations. In the Trop2 and Nectin-4 HuCell/HuGEMM studies, similar results were observed. HuGEMM models demonstrated superior positive cell rate and single-cell antigen expression levels. Furthermore, a synergistic effect was observed when PD-1 therapy was combined with monotherapy. Conclusion: HuCell and HuGEMM models provide an advanced platform to evaluate ADC drug monotherapy and combination therapies with immune checkpoint inhibitors. Additionally, they offer a sophisticated solution to assess both on-target and off-target toxicity of ADCs. Citation Format: Xiaoze Wang, Rong Wang, Kaixia Lian, Rongfei Lu, Jian Feng, Jun Zhou, Xiaolong Tu, Xinhe Feng, Jie Lin, Fuping Xu, Ludovic Bourre, Jingjing Wang. Novel humanized cell and murine models expressing tumor-associated antigens for ADC toxicity and IO combination evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7270.

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