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Mini-PBPK-Based Population Model and Covariate Analysis to Assess the Complex Pharmacokinetics and Pharmacodynamics of RO7449135, an Anti-KLK5/KLK7 Bispecific Antibody in Cynomolgus Monkeys

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Abstract

RO7449135, an anti-kallikrein (KLK)5/KLK7 bispecific antibody, is in development as a potential therapy against Netherton’s syndrome (NS). In cynomolgus monkey studies, RO7449135 bound to KLK5 and KLK7, causing considerable accumulation of total KLKs, but with non-dose-proportional increase. To understand the complex PKPD, a population model with covariate analysis was developed accounting for target binding in skin and migration of bound targets from skin to blood. The covariate analysis suggested the animal batch as the categorical covariate impacting the different KLK5 synthesis rates between the repeat-dose study and single-dose study, and the dose as continuous covariate impacting the internalization rate of the binary and ternary complexes containing KLK7. To comprehend the mechanism underlying, we hypothesized that inhibition of KLK5 by RO7449135 prevented its cleavage of the pro-enzyme of KLK7 (pro-KLK7) and altered the proportion between pro-KLK7 and KLK7. Besides the pro-KLK7, RO7449135 can interact with other proteins like LEKTI through KLK7 connection in a dose-dependent manner. The different high-order complexes formed by RO7449135 interacting with pro-KLK7 or LEKTI-like proteins can be subject to faster internalization rate. Accounting for the dose and animal batch as covariates, the model-predicted free target suppression is well aligned with the visual target engagement check. The population PKPD model with covariate analysis provides the scientific input for the complex PKPD analysis, successfully predicts the target suppression in cynomolgus monkeys, and thereby can be used for the human dose projection of RO7449135.

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Data Availability

The authors confirm that the data supporting the study are available upon request.

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Acknowledgements

We would like to thank Saroja Ramanujan, Rajbharan Yadav, and Gautham Gampa for helpful discussion on model and manuscript. We would also like to thank Anshin BioSolutions for editorial assistance.

Funding

This work was financially supported by Genentech Inc.

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Authors and Affiliations

  1. Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Hao Cai, Xun Tao & Eric Stefanich

  2. BioAnalytical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Jeongsup Shim, Wei Bu, Jason LaMar, Rachel Basile & Gizette Sperinde

  3. OMNI Biomarker Development, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Rebecca N. Bauer & Meire Bremer

  4. Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Edward Dere, Tien Nguyen & Steven Laing

  5. Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Pamela Chan

  6. Discovery Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Tangsheng Yi

  7. Antibody Engineering, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    James T. Koerber

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  1. Hao Cai
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Contributions

Participated in research design: Cai, Bauer, Dere, Nguyen, Laing, Sperinde, Stefanich.

Sample analyses: Shim, Bremer, Bu, LaMar, Basile, Chan.

Data interpretation: Cai, Tao.

PKPD model: Tao.

Corresponding author

Correspondence to Eric Stefanich.

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Conflict of Interest

All the authors are current employees of Genentech Inc.

Ethics Committee

Animals in cynomolgus monkey studies were housed in animal facilities that are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care. All procedures in the studies were approved by the local Institutional Animal Care and Use Committee.

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Hao Cai and Xun Tao are co-contributing first authors.

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Cai, H., Tao, X., Shim, J. et al. Mini-PBPK-Based Population Model and Covariate Analysis to Assess the Complex Pharmacokinetics and Pharmacodynamics of RO7449135, an Anti-KLK5/KLK7 Bispecific Antibody in Cynomolgus Monkeys. AAPS J 25, 64 (2023). https://doi.org/10.1208/s12248-023-00829-y

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