Frontiers in Pharmacology (Jun 2024)

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
https://doi.org/10.3389/fphar.2024.1380000
Journal volume & issue
Vol. 15

Abstract

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IntroductionInterleukin 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.MethodsWe 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.ResultsThe 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.ConclusionThis 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.

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