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Developing a mechanistic translational PK/PD model for a trifunctional NK cell engager to predict the first-in-human

Siak-Leng Choi1, Delphine Valente1, Angela Virone-Oddos2

  • 1Sanofi, DMPK, Paris, France.

Clinical and Translational Science
|November 22, 2023
PubMed

Insights

Researchers developed a novel translational model for natural killer cell engagers (NKCEs) to estimate first-in-human doses. This model integrates in vitro and in vivo data to predict clinical outcomes for CD123-NKCEs, advancing innate immunity therapeutics.

Area of Science:

  • Immunology
  • Pharmacology
  • Translational Medicine

Background:

  • Natural killer cell engagers (NKCEs) show promise in stimulating innate immunity with favorable safety and efficacy.
  • NK cell activation relies on immune synapse formation between drugs, NK cells, and tumor cells.
  • A clear translational modeling approach for first-in-human (FIH) dose estimation of humanized NKCEs is lacking.

Purpose of the Study:

  • To develop the first translational mechanistic synapse-driven pharmacokinetic/pharmacodynamic (PK/PD) model for a trifunctional NKp46/CD16a-CD123 (CD123-NKCE).
  • To estimate the starting dose for the FIH trial of CD123-NKCE.

Main Methods:

  • Integrated in vitro cytotoxicity data from MOLM-13 cell lines with nonhuman primate PK and immune cell profiles.
  • Incorporated healthy human and acute myeloid leukemia patient-specific parameters.
  • Developed a PK/PD model without transit compartments to represent direct tumor cell killing by innate immunity.

Main Results:

  • Model predictions supported an intrapatient dose escalation of 10/30/100 μg/kg twice weekly as the FIH starting dose.
  • Sensitivity analyses identified CD123+ cell growth rate and maximal tumor killing rate as key uncertainties.
  • The model provides a basis for predicting clinical PK/PD data for CD123-NKCE.

Conclusions:

  • The developed translational model is the first of its kind for synapse-driven NKCEs.
  • This novel translational strategy can guide future advancements in NKCE development.
  • The model facilitates prediction of clinical PK/PD data, supporting the advancement of CD123-NKCEs.

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