Antibody-drug conjugates (ADCs) are targeted cancer therapeutics that combine a monoclonal antibody with a highly potent cytotoxic payload linked via a chemical linker, enabling selective delivery of chemotherapy directly to tumor cells while minimizing systemic toxicity.
15 ADCs have received FDA approval for treating various hematologic malignancies and solid tumors.
ADCs consist of three essential components that work synergistically.
Monoclonal antibody (mAb): This acts as a targeting vehicle. It binds to a specific antigen (protein) overexpressed on the surface of cancer cells but minimally present on healthy cells (e.g., HER2, CD30, CD33, FRα, or tissue factor).
Linker: A chemical bridge connecting the antibody to the payload. It is designed to be stable in the bloodstream to prevent premature release but cleavable inside the cell—often by lysosomal enzymes or acidic pH.
Cytotoxic payload: A highly potent drug (e.g., microtubule inhibitors like MMAE or DM1, or DNA-damaging agents like calicheamicin or PBD dimers) that would be too toxic if given systemically on its own.
The monoclonal antibody targets tumor-associated antigens expressed on cancer cell surfaces, providing specificity.
The cytotoxic payload is typically a highly potent agent—often 100-1000 times more toxic than conventional chemotherapy—that disrupts critical cellular processes such as microtubule formation (auristatins, maytansinoids) or DNA replication (topoisomerase I inhibitors).
The linker connects the antibody to the payload and can be either cleavable as activated by specific conditions like lysosomal enzymes or acidic pH, or non-cleavable, with linker stability critically affecting drug release kinetics and therapeutic efficacy.
They combine the precision of monoclonal antibodies with the cell-killing power of potent cytotoxic drugs: as “smart bombs” or “biological missiles” for tumors.
ADCs function through a multi-step process.
After intravenous delivery, the antibody component binds to its target antigen on tumor cells, forming an ADC-antigen complex that undergoes receptor-mediated endocytosis.
The complex traffics through the endosomal-lysosomal pathway where the linker is cleaved, releasing the cytotoxic payload intracellularly to induce apoptosis.
The antibody binds to the target antigen on the cancer cell surface.
The ADC-antigen complex is internalized via receptor-mediated endocytosis.
Inside the lysosome, the linker breaks, releasing the payload.
The payload disrupts essential cellular processes microtubule function or DNA integrity, leading to cancer cell death (apoptosis.
A critical feature of many modern ADCs is the bystander effect, where membrane-permeable payloads released from dying tumor cells diffuse into neighboring cells, killing antigen-negative or low-expressing cells within the heterogeneous tumor microenvironment.
Bystander effects of killing nearby antigen-negative cells via payload diffusion widens the therapeutic window compared to traditional chemotherapy, which affects rapidly dividing cells indiscriminately.
FDA-approved ADCs have demonstrated efficacy across multiple cancer types.
In breast cancer, trastuzumab emtansine (Kadcyla) and trastuzumab deruxtecan (Enhertu) target HER2-positive disease, with Enhertu also approved for HER2-low tumors—a paradigm shift that expanded treatment options for approximately 50% of breast cancer patients previously classified as HER2-negative.
Sacituzumab govitecan (Trodelvy) targets TROP2 in triple-negative and HR-positive/HER2-negative breast cancer.
In hematologic malignancies, brentuximab vedotin (Adcetris) targets CD30 in Hodgkin lymphoma and peripheral T-cell lymphomas.
Inotuzumab ozogamicin (Besponsa) targets CD22 in B-cell acute lymphoblastic leukemia.
Mylotarg (gemtuzumab ozogamicin): Targets CD33; for acute myeloid leukemia (AML).
Additional agents include tisotumab vedotin (Tivdak) for cervical cancer, mirvetuximab soravtansine (Elahere) for folate receptor-alpha positive ovarian cancer, and datopotamab deruxtecan (Datroway) for EGFR-mutated NSCLC and HR-positive/HER2-negative breast cancer.
Padcev (enfortumab vedotin): For bladder cancer.
ADCs challenges include: antigen heterogeneity within tumors, resistance mechanisms with altered internalization, increased drug efflux pumps, payload resistance, systemic toxicities- myelosuppression and payload-effects), and complex manufacturing processes.
Most clinical evidence suggests that ADC resistance is largely related to chemotherapy payload rather than body target.
Delivers potent chemo directly into cancer cells, sparing most healthy tissue and allowing use of drugs too toxic for systemic administration.
Improved therapeutic index: Potentially fewer or milder systemic side effects than conventional chemo, though not side-effect free.
Common side effects stem largely from the payload or off-target effects:
Hematologic (e.g., neutropenia, thrombocytopenia, anemia). Gastrointestinal (nausea, diarrhea, constipation). Fatigue, peripheral neuropathy, rash, or infusion reactions. Specific risks: Interstitial lung disease (ILD/pneumonitis, e.g., with some HER2-targeted ADCs like Enhertu), sinusoidal obstruction syndrome (liver toxicity with certain agents like Mylotarg or Besponsa), ocular issues, or hyperglycemia.
Premature linker cleavage or payload release can contribute to toxicities.
Patient factors like organ function influence tolerability.
Most studies suggest limited value of sequencing ADCs.
Sequencing of ADCs with similar payload classes has limited clinical value however switching payload classes may enable retained efficacy.