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Alligator’s Neo-X-Prime platform aims to enable antigen presenting cells to efficiently enhance priming of tumor neoantigen-specific T cells. We have demonstrated that binding of a CD40 x TAA bispecific antibody (bsAb) to CD40 on dendritic cells (DCs) and a tumor-associated antigen (TAA) on tumor exosomes or tumor debris leads to activation of the DC, uptake of the tumor material, cross-presentation of a tumor-derived antigen and priming of tumor antigen-specific T cells. This has the potential to result in an increased quantity and/or quality of the tumor-targeting T cell pool and enhanced anti-tumor activity. Herein, we present ATOR-4066, a Neo-X-Prime bsAb targeting CD40 and CEA (CEACAM5), a TAA highly expressed in several cancers. Using in vitro models, we have demonstrated CEA-dependent activation of CD40-expressing cells, and an ability to mediate co-localization of CEA-expressing tumor debris and CD40 expressing antigen presenting cells. In addition, ATOR-4066 was shown to activate CD40-expressing cells in the presence of primary human tumor cells from CEA+ colorectal and gastric cancer patients. Furthermore, in vitro treatment of primary colorectal and gastric tumor-derived cell cultures and tumoroids with ATOR-4066 induced activation of tumor-infiltrating immune cells. In vivo studies using human CD40 transgenic mice bearing CEA-transfected MC38 tumors showed superior anti-tumor effects of ATOR-4066 compared to a CD40 mAb, demonstrating the ability of ATOR-4066 to efficiently induce a tumor-targeting immune response. Overall, these data show the ability of ATOR-4066 to remodel the immune microenvironment and activate tumor-infiltrating immune cells in primary human tumors expressing CEA, demonstrating the promise of this new candidate drug for further clinical development. Citation Format: Karin Hägerbrand, Anette Sundstedt, Mattias Levin, Yago Pico de Coaña, Laura Varas, Lill Ljung, Anneli Nilsson, Mona Celander, David Gomez Jimenez, Hampus Andersson, Malin Lindstedt, Peter Ellmark. ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEA, activates myeloid cells in primary human tumors in vitro and induces anti-tumor immunity in vivo [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 2939. |
