Bacteria found within the tumour microenvironment are capable of expressing proteins that interfere with ADC binding.
Abstract
Antibody-drug conjugates (ADCs) are a novel class of cancer therapeutic that leverages antibody-antigen specificity to deliver a highly cytotoxic payload in a precision-targeted manner. The development of effective ADCs for cancer therapy remains an unmet clinical need. Though highly effective in certain indications, only 13 ADCs have been approved by the FDA, with over 90 discontinued after clinical testing (Maecker et al., 2023; Liu et al., 2024). Theorised mechanisms of ADC resistance and toxicity include lack of target antigen expression on tumour cells, early off-target linker cleavage, impaired ADC internalisation, and lysosomal degradation defects (Abelman et al., 2023; Khoury et al., 2023; Nguyen, Bordeau and Balthasar, 2023).
Bacteria have been established to be present in the tumour microenvironment (TME) (Nejman et al., 2020a) and have been shown to functionally impact a variety of systemic anticancer treatments, including small-molecule inhibitors (Geller et al., 2017). We hypothesise that intratumoral drug-bacteria interactions extend to ADCs, providing novel evidence of receptor-binding competition by bacterial proteins in the case of CEACAM5-directed ADCs, such as tusamitamab ravtansine. These interactions have potential implications for the pharmaceutical development and clinical deployment of ADCs and possibly explain the recent failure of several late-phase clinical trials.
Our broader aim is to construct a comprehensive framework for understanding drug-bacteria interactions in the context of ADCs. This is supported by preliminary data suggesting that bacterial interactions can occur with the three major molecular components of ADCs, the antibody, the payload and the linker. Using our unique foundational emulator, Carbon Mirror, we can run in silico trials that model the impact of these interactions on relevant patient subgroups, providing valuable insights for the development of pipeline assets.
