Immunocytokines (IC) leverage orthogonal mechanisms of action in one molecule to induce potent antitumor immune responses. PD-1-targeting ICs are of particular interest since they harbor the multifunctional ability to selectively target antigen-experienced PD-1+ CD8+ T cells enriched in the tumor microenvironment (TME), release them from PD-(L)1 pathway inhibition, be retained within the TME, and simultaneously deliver potent cytokine receptor stimulation to the same T cell in cis (cis-signaling).

Interleukin (IL-18) is a proinflammatory cytokine that stimulates both innate and adaptive immunity and generates potent antitumor activity mediated by both T effector and NK cells. Recent evidence indicates that a subset of tumor-infiltrated PD-1+ CD8+ T effector cells hallmarked by high expression of IL-18 receptor exhibits a superior cytotoxic and proliferative phenotype. Hence, we developed a PD1-IL18 IC to specifically target and activate intratumoral IL-18R-expressing PD-1+ CD8+ T cells.

We engineered a conjugatable variant of human IL-18 with enhanced potency and significant resistance to IL-18 binding protein (IL-18BP) and utilized this enhanced IL-18 payload to create a PD1-IL18 IC (BPT567) via site-specific chemical conjugation to a defined lysine residue within the heavy chain of an anti-human PD-1 antibody (Ab). Conjugation did not affect the basic properties of the Ab as neither binding to PD-1 nor the interaction with the neonatal Fc receptor (FcRn) or Fcγ receptors were significantly impacted. Of note, the conjugation handle in our enhanced IL-18 variant was inserted at a site distinct from its N- or C-terminus to preserve the full potency and selectivity of the IL-18 payload. As a result, BPT567 exhibits increased potency and marked resistance to IL-18BP inhibition compared to wild-type IL-18.

In vivo, BPT567 shows striking antitumor efficacy in multiple syngeneic mouse tumor models that is superior to responses induced by an anti-PD-1 Ab alone, a non-targeted IL-18 IC or the combination of both agents. Our evidence suggests that the strong in vivo efficacy observed is attributed to a preferential activation of PD-1+ tumor-infiltrated immune cells. The excellent tolerability and large therapeutic window observed in mice may be driven by less potent immune cell activation in the periphery.

Citation Format: Jean-Philippe Carralot, Kea Martin, Rubén Alvarez Sanchez, Roy Meoded, Caoimhe Herr, Philipp Moosman, Arnaud Goepfert, Andrew Chi, Vijaya J. Pattabiraman, Bertolt Kreft. A first-in-class PD1-IL18 immunocytokine (BPT567) targets PD-1+ IL18R+ CD8+ T effector cells enriched in the tumor microenvironment and exhibits potent antitumor efficacy with excellent tolerability [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 1850.