Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody–Drug Conjugates to IncreaseIn VivoEfficacy

Abstract

Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRa). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear. An antibody that cross-reacts with human and murine FRa was generated and tested in an animal model where the antibody/ADC bind both human tumor FRa and mouse FRa in normal tissue. Previous work has demonstrated that a "carrier" dose of unconjugated antibody can improve the tumor penetration of ADCs with high expression target-antigens. A carrier dose was employed to study the impact on cross-reactive ADC clearance, distribution, and efficacy. Co-administration of unconjugated anti-FRa antibody with the ADC-improved efficacy, even in low expression models where co-administration normally lowers efficacy. By reducing target-antigen-mediated clearance in normal tissue, the coadministered antibody increased systemic exposure, improved tumor tissue penetration, reduced target-antigen-mediated uptake in normal tissue, and increased ADC efficacy. However, payload potency and tumor antigen saturation are also critical to efficacy, as shown with reduced efficacy using too high of a carrier dose. The judicious use of higher antibody doses, either through lower DAR or carrier doses, can improve the therapeutic window by increasing efficacy while lowering target-mediated toxicity in normal tissue.

Targeting cancer with antibody-drug conjugates: Promises and challenges

“…This notion was supported by in vitro studies involving coadministration of DAR0 or the naked antibody. 156,157 Novel site-specific conjugation methods using unique linker chemistries that yield homogenous ADCs of desired DARs have emerged. 107 One technique involves installing natural or unnatural amino acids into the antibody sequence for strict control over DAR and DLD.…”

Predictive Simulations in Preclinical Oncology to Guide the Translation of Biologics

“…The antigen expression of Nectin-4 on T47D cells is lower than HER2 and Trop2, and an 18 h estimated internalization half-life ( Supplementary Table S1 ) allows ADC molecules to quickly occupy the receptor binding sites on cell surface before they are internalized. The Thiele modulus of Mirvetuximab soravtansine is below 1 due to the low FR-internalization and recycling rate ( Monteiro et al, 2020 ; Ponte et al, 2021 ). Although there’s an antibody-dependent downmodulation of TF surface expression, the Thiele modulus of Tivdak is greater than 1, consistent with heterogeneous distribution of tissue factor antibodies seen in some animal models ( de Goeij et al, 2015 ; Koga et al, 2015 ).…”

Design of high avidity and low affinity antibodies for in situ control of antibody drug conjugate targeting

“…The spheroid model does not capture vascular permeability 33 , plasma clearance, and payload distribution following release. Therefore, the competition model was adapted to a previously validated Krogh Cylinder geometry to simulate ADC and Payload distribution in vascularized tumors 5 , 11 , 25 , 28 , 34 , 35 . The Krogh Cylinder model assumes radial but not axial distribution because concentration varies little along the capillary length 36 .…”

“…While increasing the dose is a well-known technique for more homogenous distribution of antibodies, ADC doses are limited by toxicity due to their payload 9 , 10 . One method for expanding the therapeutic window is to decrease the potency of ADCs for high expression targets 11 . This enables higher dosing that can increase the tissue penetration of the ADC in the tumor, reaching and killing more cells, while also lowering the target-mediated uptake of ADCs in healthy tissue, reducing toxicity 11 .…”

“…One method for expanding the therapeutic window is to decrease the potency of ADCs for high expression targets 11 . This enables higher dosing that can increase the tissue penetration of the ADC in the tumor, reaching and killing more cells, while also lowering the target-mediated uptake of ADCs in healthy tissue, reducing toxicity 11 . Another strategy is using site specific conjugation, where the payload is conjugated to a specific site of the antibody using a chemical or enzymatic methods 12 – 14 .…”