Abstract 3133: PF-08046032: a CD25-directed vedotin ADC leveraging a well characterized safety and pharmacokinetic profile for enhanced regulatory T cell depletion in the tumor microenvironment

Abstract PF-08046032 is a novel vedotin antibody-drug conjugate (ADC) engineered to target and deplete immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) through direct cytotoxicity. PF-08046032 directs delivery of the cytotoxic MMAE (monomethyl auristatin E) vedotin payload to cells expressing CD25, the alpha chain of the IL-2 receptor, which is highly expressed on intratumoral Tregs and lymphoma cells. The MMAE-based vedotin drug linker platform, utilized in four approved ADCs for hematologic and solid tumors, has a well-characterized mechanism of action (MoA), exposure, and target-independent toxicity profile. PF-08046032 leverages this platform, exerting anti-tumor activity through the multifaceted MMAE-driven MoA, including direct cytotoxicity, bystander killing, and immunogenic cell death. Additionally, PF-08046032 is differentiated from other vedotin ADCs and anti-CD25 depleting agents through affinity-tuned binding, which enables selective targeting of CD25hi intratumoral Tregs while sparing peripheral Tregs. Here, we present preclinical data demonstrating safety, pharmacokinetics, and anti-tumor activity of PF-08046032 which is highly consistent with the vedotin ADC platform, while additionally harnessing a Treg-directed anti-tumor approach. PF-08046032 selectively kills Tregs compared to CD8 T cells, with preferential activity on Tregs with the highest CD25 expression and shows dose-dependent antitumor activity in CD25-expressing lymphoma xenograft models. In human CD25-expressing mice bearing MC38 colorectal carcinoma tumors, PF-08046032 significantly suppressed intratumoral Treg levels with minimal activity on peripheral Tregs and no effect on intratumoral CD8+ T cells. A mouse surrogate of PF-08046032 demonstrated that targeted depletion of immunosuppressive tumoral Tregs resulted in robust antitumor activity as both a single agent and in combination with anti-PD1 checkpoint inhibitor blockade. Pharmacokinetic and toxicity studies in non-human primates demonstrated safety and PK profiles consistent with the vedotin platform despite targeting CD25. Leveraging the cumulative knowledge of the vedotin platform, PF-08046032 enables a novel additional mechanism of action for vedotin ADCs at potentially efficacious and safe doses. These data support further investigation of PF-08046032 in clinical trials for advanced malignancies. Citation Format: Christopher Carosino, Sherif Abdelhamed, Priyanka Gupta, Xinqun Zhang, Bryan Grogan, Weiping Zeng, Lauren Bou, Devra Olson, Paromita Raha, Andrea R. Lim, Brian P. O'Connor, Ryan A. Heiser, Matthew R. Levengood. PF-08046032: a CD25-directed vedotin ADC leveraging a well characterized safety and pharmacokinetic profile for enhanced regulatory T cell depletion in the tumor microenvironment [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 3133.