527 Preclinical dose-pharmacokinetic-efficacy modeling of botensilimab using a mouse surrogate of the Fc-enhanced anti-CTLA-4 antibody
Year: 2024
Type: conference-abstract
Abstract: Background CTLA-4 antagonist antibodies were the first immune checkpoint inhibitors demonstrating durable clinical responses.1 However, their expansion to new indications has been limited. Preclinical murine studies have demonstrated that anti-CTLA-4 activity depends on co-engaging Fcγ receptor (FcγR)-dependent mechanisms to promote T-cell priming, Treg depletion, and myeloid activation.2 These findings extended to patients treated with botensilimab, an Fc-enhanced multifunctional anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and treatment-refractory cancers, including microsatellite stabile (MSS) colorectal cancer (CRC).3 To support the clinical development of botensilimab, we modelled efficacious doses and exposure parameters using mouse tumor models treated with a pharmacologically matched mouse surrogate antibody (botensilimabms). Methods The potency and efficacy of botensilimabmsversus a conventional CTLA-4 surrogate antibody were evaluated in the MSS CT26 CRC model. The CTLA-4 antibody, clone 9D9, engineered on a murine IgG2b Fc backbone was selected for its functional comparability to conventional human IgG1 whereas an Fc-engineered murine IgG2b, with S239D/A330L/I332E mutations was used as a surrogate for botensilimab. Dose-response relationships were assessed using single administrations. Binding affinities for CTLA-4 and FcγRs were determined by flow cytometry and surface plasmon resonance. A multi-dose pharmacokinetic (PK) study correlated drug plasma concentrations with preclinical response. PK parameters were derived using a non-compartmental analysis. Pharmacodynamic effects were assessed by flow cytometry. Results Botensilimabms demonstrated pharmacological equivalence to botensilimab, with comparable CTLA-4 binding affinities and comparable ratios of binding to activating and inhibiting Fc gamma receptors. In tumor models, botensilimabms exhibited superior efficacy and potency compared to the conventional anti-CTLA-4ms. The therapeutic dose range for botensilimabms (5 – 50 µg) was lower than that of conventional anti-CTLA-4ms (10 – 100 µg). At equivalent doses, botensilimabms elicited stronger intratumoral pharmacodynamic effects, including more pronounced Treg depletion and expansion of tumor-reactive T cell clones. Half-lives were comparable for both antibodies (50.6 hours for botensilimabms versus 55.5 hours for conventional CTLA-4ms). Exposure-response analysis revealed that the therapeutic range corresponded to average plasma concentrations (Cavg) of 1.1 – 11.1 µg/mL for botensilimabms, consistent with botensilimab’s recommended Phase 2 dose (RP2D) of 75 mg Q6W, which yielded a Cavg of 4.49 ± 1.39 µg/mL. In comparison, the Cavg range for conventional CTLA-4ms was 1.7 – 17.9 µg/mL. Conclusions This study demonstrated the enhanced potency and efficacy of an Fc-enhanced anti-CTLA-4 antibody (botensilimabms) versus conventional anti-CTLA-4 in CT26 CRC. The observed exposure-response relationship predicted the clinically efficacious doses of botensilimab, validating this modeling approach for guiding clinical development of Fc-engineered antibodies. References Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol 2005;12:1005–16. Waight JD, Chand D, Dietrich S, et al. Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens. Cancer Cell 2018;33:1033–1047. Bullock AJ, Schlechter BL, Fakih MG et al. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med 2024 (Online ahead of print). Ethics Approval Human materials were obtained following informed consent under Western Institutional Review Board® Protocol #20233227. Animal data was approved by an institutional review board Agenus-Neosome IACUC Protocols #NLS18-016 and NLS21-015.
Institution: Agenus (United States)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404065566