# Preclinical profiling of antibody drug conjugates targeting oncofetal chondroitin sulfate

## TL;DR

This study explores antibody-drug conjugates targeting oncofetal chondroitin sulfate, showing strong tumor targeting and anti-cancer effects in preclinical models.

## Contribution

The paper introduces Vartumab ADCs with bystander-capable payloads, demonstrating enhanced in vivo potency and safety for potential clinical development.

## Key findings

- Vartumab ADCs show strong tumor uptake and minimal accumulation in other organs in mice.
- Both ADCs induce bystander killing of antigen-negative cells and display potent anti-tumor activity in a melanoma model.
- ADC-MMAE is well-tolerated in rats with similar toxicities to clinically approved MMAE-conjugated ADCs.

## Abstract

Antibody-drug conjugates (ADC) offer a targeted cancer treatment approach by delivering cytotoxic payloads directly to tumor cells. However, resistance mechanisms, poor tumor penetration, and off-target toxicity often limit clinical efficacy. Vartumab targets oncofetal chondroitin sulfate (ofCS), a pan-cancer target present on tumor cells and in the malignant stroma, with low expression in normal tissues. As part of transitioning Vartumab to clinical evaluation, two linker-payloads known to mediate bystander effects, valine-citrulline (vc)—monomethyl auristatin E (MMAE) and glycine-glycine-phenylalanine-glycine (ggfg)—Deruxtecan (DXd), were investigated for design of Vartumab ADCs. We show that the ADCs maintain specificity to ofCS proteoglycans, cancer cells, and tissue biopsies, exhibiting specific binding to a wide range of malignant and metastatic tissues. Biodistribution assessment of Vartumab ADCs in mice shows strong and specific tumor uptake, with minimal accumulation in other organs. Both ADCs induced bystander killing of antigen-negative cells in the presence of antigen-positive cells and displayed potent anti-tumor activities in a cell-derived xenograft melanoma model. Furthermore, we show that Vartumab conjugates with bystander-capable linker-payloads exhibit greater in vivo potency compared to those with payloads lacking significant bystander effect. Finally, toxicity assessment in rats indicates that the ADC-MMAE is well-tolerated upon repeated doses, with similar dose-limiting toxicities as reported for clinically approved MMAE-conjugated ADCs. Our data support further clinical development of Vartumab-based ADCs.