Abstract LB440: Quantitative Systems Pharmacology (QSP) enables research and translation of AMP01, a novel next generation anti PD1 bispecific that amplifies and redirects endogenous IL15 to PD1 high expressing T Cells, maximizing efficacy and therap

Abstract Background: Safe and efficacious dosing of clinically validated cytokines is exciting but remains elusive. The primary challenge has been therapeutic index (TI), i.e. providing sufficient cytokine tumor exposure while minimizing exposure elsewhere to avoid systemic immune activation. Prior attempts to address this, including engineered IL15-fusion proteins (FP) and PD1 x IL15 bispecific-FPs, have been limited by toxicity and development of anti-drug antibodies. AMP01, an anti PD1 x anti IL15 bispecific biologic, is a novel solution to this challenge. It is designed to capture and redirect endogenous IL15 to PD1high expressing T Cells, thus providing PD1 inhibition and targeted delivery of IL15 to the tumor and tumor microenvironment. By design, AMP01 promises to be a truly improved next generation PD1 program with both checkpoint inhibitory and targeted immune agonistic activity. Method: We developed a QSP model by leveraging AMP01 in vitro, mouse, and non-human primate data, and previously published anti PD1, IL15-FP, and IL15 x PD1-FP pharmacokinetic (PK) and pharmacodynamic (PD) data. The model also incorporates complex biology and drug MOA, e.g., IL15 synthesis and clearance; IL15 soluble and membrane bound receptor binding; alterations in IL15 exposure; IL15 mediated NK and T Cell dynamics; PD1 PK and PD1 inhibition; and dynamic target mediated drug disposition. The model described the PK and observed cell dynamics in the plasma, and simulated effects in tumor and other peripheral tissue of comparator therapeutics and AMP01. Results: The model 1) informed AMP01 design and candidate selection by predicting optimal AMP01 binding characteristics to maximize TI and efficacy by selectively targeting PD1 high, IL15 receptor expressing immune cells while maintaining high PD1 coverage in the tumor selectively; 2) clarified how uncertainty and variability in model parameters (e.g., soluble IL15 and IL15 receptor concentration; membrane bound receptor expression, synthesis and clearance rates; immune cell numbers and dynamics) impacts AMP01 target engagement, mediation of cytokine activity, nonlinear PK, and dosing for simulated virtual patient variability; and 3) enables in silico comparator differentiation to better understand safe and efficacious dosing and variability using simulated cell dynamics in the blood, tumor, and other periphery compartments. This model continues to be developed and will be used to provide first in human dose predictions to impact IND, regulatory decisions, and phase 1 trial design. Conclusions: The model accelerated the design and selection of AMP01, a potentially best in class next-generation multi-functional anti-PD1 therapy and provided insights into the complexity of IL15 mediated immune cell dynamics to better understand safety and efficacy for simulated virtual patient variability. Citation Format: John M. Burke, Abhishek Mukhopadhyay, Mark Fogg, Stacey Tom-Yew, Harsh Pratap, David Flowers, Diana Marcantonio, Sarah Minucci, Diana Hausman, David de Graaf, Surjit Dixit. Quantitative Systems Pharmacology (QSP) enables research and translation of AMP01, a novel next generation anti PD1 bispecific that amplifies and redirects endogenous IL15 to PD1 high expressing T Cells, maximizing efficacy and therapeutic index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB440.