(M1030-02-07) Pharmacokinetic/Pharmacodynamic Insights into VSIG4 Degrading Antibodies

Purpose: This study seeks to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of innovative antibodies targeting VSIG4, a myeloid-specific immune checkpoint molecule. VSIG4 is primarily expressed in resident-tissue macrophages (RTMs), where it plays a critical role in suppressing T-cell activation and proliferation, thereby contributing to immune evasion in cancer [1,2]. By employing antibody-mediated degradation, this research explores the potential to disrupt VSIG4-mediated immune suppression and enhance anti-tumor immune responses. The study aims to identify the PK parameters that correlate with effective VSIG4 degradation to optimize dosing strategies for maximizing therapeutic efficacy.

Methods: An antibody campaign led to the identification of potent candidates. THP1-VSIG4/HiBiT cells were used to assess antibody-mediated VSIG4 degradation in vitro, with subsequent validation in primary macrophage cultures derived from monocytes. Genetic knockout (KO) models were employed to elucidate the role of VSIG4 in tumor burden reduction. A dose-ranging pharmacokinetic study was performed in mice to understand exposure and behavior related to target-mediated drug disposition [3]. Finally, an in vivo comprehensive PK/PD study was then performed to assess the PK drivers for VSIG4 degradation.

Results: The most effective antibodies were identified through comprehensive in vitro screening, which prioritized candidates that achieved the greatest degradation of VSIG4 levels in both THP1-VSIG4/HiBiT cells and primary macrophage cultures. A dose-ranging PK study revealed target-mediated drug disposition (TMDD) behavior at low antibody doses, indicating a saturation of VSIG4 binding sites and highlighting the importance of dose optimization to maximize therapeutic efficacy. The integrated PK/PD study revealed a clear threshold concentration above which VSIG4 degradation was observed (Figure 1).

Conclusion: The findings underscore the potential of VSIG4-targeting antibodies in modulating immune responses and how an understanding of the PK/PD relationship may lead to optimized dosing regimens. Future studies will aim to confirm efficacy in preclinical tumor models with this novel therapeutic approach and further optimize the antibody design to maximize clinical benefits.

References: 1. Yuan, Xiaomei, et al. "CRIg, a tissue-resident macrophage specific immune checkpoint molecule, promotes immunological tolerance in NOD mice, via a dual role in effector and regulatory T cells." Elife 6 (2017): e29540.
2. Huang, Xiaoyong, et al. "VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1 β in macrophages." Science advances 5.1 (2019): eaau7426.
3. Kamath, Amrita V. "Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies." Drug Discovery Today: Technologies 21 (2016): 75-83.

Acknowledgements: All authors are full-time employees at Genentech, Inc. The authors declared no competing interests for this work.

Figure 1. (A) Pharmacokinetics of VSIG4 degrading and control antibodies in mice. (B) VSIG4 expression in liver Kupffer cells across time. (C) VISG4 expression returns when systemic concentrations are below 1 ug/mL.