Advances in the Development of Dual-Drug Antibody Drug Conjugates

Antibody drug conjugates (ADCs) are touted for their ability to site selectively deliver a small molecule chemotherapeutic directly to a tumor cell, bypassing off target side effects from systemic circulation. To date, twelve ADCs have been FDA approved in the United States and >200 more in the clinical pipeline. While ADCs have proven successful in both solid and hematological cancers, resistance and tumor heterogeneity are major causes of failure clinically.[1] Tumor heterogeneity is known to lead to recurrence, metastasis, and acquired resistance to ADCs and other therapeutic strategies. Heterogenous tumors with differential drug sensitivities result in aggressive tumor growth, high relapse rates, and poor survival. To combat these challenges, the majority of chemotherapeutic regimens consist of a combination of drugs. Co-delivery of small molecules can overcome resistance, generate additive or synergistic effects, and enhance therapeutic efficacy. Emergence of tumors refractory to current therapies has given impetus to the evaluation of new ADC formats. This challenge has led to the exploration of dual-drug ADCs capable of delivering two mechanistically distinct payloads simultaneously. Strategies for the construction of dual-drug ADCs involve attachment of both drugs to one linker or through the use of two different conjugation sites on the antibody. Herein, we will review the synthesis and evaluation of the dual-drug ADCs reported to date. We focus on ADCs constructed by conjugation of linkers directly to antibody scaffolds and not to other formats or targeting molecules.