Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence

SIMPLE SUMMARY: Antibody–drug conjugates (ADC) have shown remarkable therapeutic activity in a wide range of hematologic and solid tumors. Herein, we discuss the mechanisms of action of ADCs, the desirable “bystander killing”, and the limitations associated with the design of each drug. We will also discuss the landmark clinical trials that demonstrated their treatment efficacy in each indication and that have been approved for clinical use by the Food and Drug Administration (FDA). We will also discuss unique side effects which are tied to the normal tissue expression of the antigen, the intrinsic toxicity of the payload, and the off-target toxicity. Finally, we will discuss some exciting new developments in the pipeline, including peptide–drug conjugates, immune-stimulating drug conjugates, and radioactive isotopes as payloads. ABSTRACT: Antibody–drug conjugates (ADCs) are an innovative family of agents assembled through linking cytotoxic drugs (payloads) covalently to monoclonal antibodies (mAbs) to be delivered to tumor tissue that express their particular antigen, with the theoretical advantage of an augmented therapeutic ratio. As of June 2023, eleven ADCs have been approved by the Food and Drug Administration (FDA) and are on the market. These drugs have been added to the therapeutic armamentarium of acute myeloblastic and lymphoblastic leukemias, various types of lymphoma, breast, gastric or gastroesophageal junction, lung, urothelial, cervical, and ovarian cancers. They have proven to deliver more potent and effective anti-tumor activities than standard practice in a wide variety of indications. In addition to targeting antigen-expressing tumor cells, bystander effects have been engineered to extend cytotoxic killing to low-antigen-expressing or negative tumor cells in the heterogenous tumor milieu. Inevitably, myelosuppression is a common side effect with most of the ADCs due to the effects of the cytotoxic payload. Also, other unique side effects are specific to the tissue antigen that is targeted for, such as the cardiac toxicity with Her-2 targeting ADCs, and the hemorrhagic side effects with the tissue factor (TF) targeting Tisotumab vedotin. Further exciting developments are centered in the strategies to improve the tolerability and efficacy of the ADCs to improve the therapeutic window; as well as the development of novel payloads including (1) peptide–drug conjugates (PDCs), with the peptide replacing the monoclonal antibody, rendering greater tumor penetration; (2) immune-stimulating antibody conjugates (ISACs), which upon conjugation of the antigen, cause an influx of pro-inflammatory cytokines to activate dendritic cells and harness an anti-tumor T-cell response; and (3) the use of radioactive isotopes as a payload to enhance cytotoxic activity.