Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy

Rajbharan Yadav; Suzanne Schubbert; Patrick G Holder; Eugene Y Chiang; Nargess Kiabi; Liz Bogaert; Irene Leung; Rumana Rashid; Kendra N Avery; Christine Bonzon; John R Desjarlais; Shomyseh Sanjabi; Amy Sharma; Michelle Lepherd; Amy Shelton; Pam Chan; Yanqiu Liu; Louis Joslyn; Iraj Hosseini; Eric G Stefanich; Amrita V Kamath; Matthew J Bernett; Vittal Shivva

doi:10.3389/fphar.2024.1380000

Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy

Front Pharmacol. 2024 Jun 3:15:1380000. doi: 10.3389/fphar.2024.1380000. eCollection 2024.

Authors

Rajbharan Yadav^#¹, Suzanne Schubbert^#², Patrick G Holder¹, Eugene Y Chiang¹, Nargess Kiabi², Liz Bogaert², Irene Leung², Rumana Rashid², Kendra N Avery², Christine Bonzon², John R Desjarlais², Shomyseh Sanjabi¹, Amy Sharma¹, Michelle Lepherd¹, Amy Shelton¹, Pam Chan¹, Yanqiu Liu¹, Louis Joslyn¹, Iraj Hosseini¹, Eric G Stefanich¹, Amrita V Kamath¹, Matthew J Bernett², Vittal Shivva¹

Affiliations

¹ Genentech, Inc., South SanFrancisco, CA, United States.
² Xencor, Inc., Pasadena, CA, United States.

^# Contributed equally.

Abstract

Introduction: Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities.

Methods: We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This "PD1/IL15" selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials.

Results: The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0-4.1 days) compared to wild-type IL-15 (half-life ∼1.1 h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1⁺ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003 mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data.

Conclusion: This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

Keywords: PD1/IL15 TaCK; first-in-human dose; minimum anticipated biological effect level; target mediated drug disposition; targeted cytokine.

Copyright © 2024 Yadav, Schubbert, Holder, Chiang, Kiabi, Bogaert, Leung, Rashid, Avery, Bonzon, Desjarlais, Sanjabi, Sharma, Lepherd, Shelton, Chan, Liu, Joslyn, Hosseini, Stefanich, Kamath, Bernett and Shivva.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The authors declare that this study received funding from Genentech and Xencor. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.