PF-08046032: A novel, investigational CD25-directed antibody-drug conjugate optimized for selective depletion of regulatory T cells in advanced malignant tumors

Abstract Regulatory T cells (Tregs) are known to suppress antitumor immune responses and their presence in the tumor microenvironment (TME) is associated with cancer progression; therefore, Treg depletion is a promising strategy to enhance cancer immunotherapy. PF-08046032 is a novel antibody-drug conjugate (ADC) designed to target Tregs in the TME via CD25, the alpha chain of the IL-2 receptor frequently upregulated by intratumoral Tregs. PF-08046032 is composed of an affinity-detuned anti-CD25 antibody linked to monomethyl auristatin E (MMAE), a potent cytotoxic agent. Affinity detuning increases PF-08046032 selectivity for CD25high intratumoral Tregs while minimizing peripheral blood Treg depletion, thus reducing the risk of autoimmune toxicities. In preclinical experiments, PF-08046032 selectively depleted Tregs compared to CD8+ T cells and preferentially depleted Tregs with high CD25 expression. PF-08046032 showed dose-dependent antitumor activity in CD25-expressing human lymphoma xenograft models, while a similarly detuned anti-mouse CD25 surrogate ADC depleted intratumoral Tregs and drove CD8+ T cell activation in murine tumor models. This effect resulted in robust antitumor activity as a single agent and in combination with anti-PD1 checkpoint inhibitor blockade. Lastly, PF-08046032 was well-tolerated in non-human primates and mitigated the persistent depletion of peripheral blood Treg that was observed with a high affinity anti-CD25 ADC comparator, demonstrating the safety benefit of a detuned affinity ADC format. PF-08046032 represents an innovative therapeutic approach for depletion of intratumoral Tregs that may offer an improved safety profile and efficacy over traditional Treg depleting agents.