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

被引：0

作者：

Yadav, Rajbharan ^{[1
]}

Schubbert, Suzanne ^{[2
]}

Holder, Patrick G. ^{[1
]}

Chiang, Eugene Y. ^{[1
]}

Kiabi, Nargess ^{[2
]}

Bogaert, Liz ^{[2
]}

Leung, Irene ^{[2
]}

Rashid, Rumana ^{[2
]}

Avery, Kendra N. ^{[2
]}

Bonzon, Christine ^{[2
]}

Desjarlais, John R. ^{[2
]}

Sanjabi, Shomyseh ^{[1
]}

Sharma, Amy ^{[1
]}

Lepherd, Michelle ^{[1
]}

Shelton, Amy ^{[1
]}

Chan, Pam ^{[1
]}

Liu, Yanqiu ^{[1
]}

Joslyn, Louis ^{[1
]}

Hosseini, Iraj ^{[1
]}

Stefanich, Eric G. ^{[1
]}

Kamath, Amrita V. ^{[1
]}

Bernett, Matthew J. ^{[2
]}

Shivva, Vittal ^{[1
]}

机构：

[1] Genentech Inc, South San Francisco, CA 94080 USA

[2] Xencor Inc, Pasadena, CA 91107 USA

来源：

FRONTIERS IN PHARMACOLOGY | 2024年 / 15卷

关键词：

targeted cytokine; PD1/IL15; TaCK; minimum anticipated biological effect level; first-in-human dose; target mediated drug disposition; FDA ONCOLOGY ANALYSIS; IL-15; PHARMACOKINETICS; INTERLEUKIN-15; LYMPHOCYTES; ANTIBODIES; IL15;

D O I：

10.3389/fphar.2024.1380000

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 similar to 1.0-4.1 days) compared to wild-type IL-15 (half-life similar to 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.

引用

页数：14

共 2 条

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