Preclinical and translational pharmacology of afucosylated anti-CCR8 antibody for depletion of tumour-infiltrating regulatory T cells

Gautham Gampa; Phillip Spinosa; Jennifer Getz; Yu Zhong; Wendy Halpern; Emel Esen; John Davies; Cassie Chou; Mandy Kwong; Yingyun Wang; Teresita L Arenzana; Vittal Shivva; Mahrukh Huseni; Robert Hsieh; Jill Schartner; James T Koerber; Sascha Rutz; Iraj Hosseini

doi:10.1111/bph.16326

Preclinical and translational pharmacology of afucosylated anti-CCR8 antibody for depletion of tumour-infiltrating regulatory T cells

Br J Pharmacol. 2024 Mar 14. doi: 10.1111/bph.16326. Online ahead of print.

Authors

Gautham Gampa¹, Phillip Spinosa¹, Jennifer Getz², Yu Zhong³, Wendy Halpern³, Emel Esen⁴, John Davies³, Cassie Chou⁵, Mandy Kwong⁶, Yingyun Wang⁷, Teresita L Arenzana⁸, Vittal Shivva¹, Mahrukh Huseni⁴, Robert Hsieh⁵, Jill Schartner⁷, James T Koerber⁹, Sascha Rutz⁸, Iraj Hosseini¹

Affiliations

¹ Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, California, USA.
² Department of Bioanalytical Sciences, Genentech, Inc., South San Francisco, California, USA.
³ Department of Safety Assessment, Genentech, Inc., South San Francisco, California, USA.
⁴ Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California, USA.
⁵ Department of Early Clinical Development, Genentech, Inc., South San Francisco, California, USA.
⁶ Department of Biochemical Cellular Pharmacology, Genentech, Inc., South San Francisco, California, USA.
⁷ Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.
⁸ Department of Cancer Immunology, Genentech, Inc., South San Francisco, California, USA.
⁹ Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, USA.

PMID: 38486310
DOI: 10.1111/bph.16326

Abstract

Background and purpose: RO7502175 is an afucosylated antibody designed to eliminate C-C motif chemokine receptor 8 (CCR8)⁺ Treg cells in the tumour microenvironment through enhanced antibody-dependent cellular cytotoxicity (ADCC).

Experimental approach: We report findings from preclinical studies characterizing pharmacology, pharmacokinetics (PK)/pharmacodynamics (PD) and safety profile of RO7502175 and discuss the translational PK/PD approach used to inform first-in-human (FiH) dosing strategy and clinical development in solid tumour indications.

Key results: RO7502175 demonstrated selective ADCC against human CCR8⁺ Treg cells from dissociated tumours in vitro. In cynomolgus monkeys, RO7502175 exhibited a biphasic concentration-time profile consistent with immunoglobulin G1 (IgG1) antibodies, reduced CCR8⁺ Treg cells in the blood, induced minimal and transient cytokine secretion, and was well tolerated with a no-observed-adverse-effect level (NOAEL) of 100 mg·kg^-1 . Moreover, RO7502175 caused minimal cytokine release from peripheral blood mononuclear cells (PBMCs) in vitro. A quantitative model was developed to capture surrogate anti-murine CCR8 antibody PK/PD and tumour dynamics in mice and RO7502175 PK/PD in cynomolgus monkeys. Subsequently, the model was used to project RO7502175 human PK and receptor occupancy (RO) in patients. Because traditional approaches resulted in a low FiH dose for this molecule, even with its superior preclinical safety profile, an integrated approach based on the totality of preclinical data and modelling insights was used for starting dose selection.

Conclusion and implications: This work demonstrates a translational research strategy for collecting and utilizing relevant nonclinical data, developing a mechanistic PK/PD model and using a comprehensive approach to inform clinical study design for RO7502175.

Keywords: CCR8; first-in-human dose; minimal PBPK modelling; pharmacokinetics (PK)-pharmacodynamics (PD); regulatory T (Treg) cells.

Grants and funding

Genentech