Antibody–Drug Conjugates (ADCs)
Definition:
ADCs are targeted cancer therapies that combine:
- A monoclonal antibody → recognizes a tumor-associated antigen.
- A linker → connects the antibody to the payload, ideally stable in circulation but cleavable inside tumor cells.
- A cytotoxic payload (“warhead”) → highly potent chemotherapy (e.g., microtubule inhibitor, DNA-damaging agent) delivered directly to cancer cells.
This design increases tumor selectivity while limiting systemic toxicity compared to conventional chemotherapy.
Mechanism of Action
- Binding: ADC antibody binds to a specific antigen on tumor cells.
- Internalization: The antigen-ADC complex is internalized into the cell via endocytosis.
- Payload Release: Linker is cleaved (enzymatic or pH-sensitive) inside the lysosome.
- Cytotoxic Effect: Payload kills the tumor cell (e.g., DNA damage, mitotic arrest).
- Bystander Effect: Some ADCs release payload into the tumor microenvironment → can kill neighboring antigen-negative cells.
Key Components
- Antibody: Provides specificity (e.g., anti-CD19, anti-HER2, anti-CD22).
- Linker:
- Cleavable: sensitive to pH, proteases, or glutathione (e.g., hydrazone, peptide).
- Non-cleavable: requires complete degradation of antibody.
- Payload (Warhead): Extremely potent chemo drugs (much stronger than standard agents):
- Microtubule inhibitors: MMAE, MMAF, DM1 (maytansinoids).
- DNA-damaging agents: Calicheamicin, PBD dimers.
- Topoisomerase I inhibitors: SN-38 derivatives.
Examples of FDA-Approved ADCs in Oncology
| Drug (Target) | Brand Name | Target Antigen | Payload | Indications |
|---|---|---|---|---|
| Brentuximab vedotin | Adcetris | CD30 | MMAE (microtubule inhibitor) | Hodgkin lymphoma, ALCL |
| Inotuzumab ozogamicin | Besponsa | CD22 | Calicheamicin | Relapsed/refractory B-ALL |
| Trastuzumab emtansine (T-DM1) | Kadcyla | HER2 | DM1 (maytansinoid) | HER2+ breast cancer |
| Trastuzumab deruxtecan (T-DXd) | Enhertu | HER2 | Deruxtecan (topo-I inhibitor) | HER2+ and HER2-low breast cancer, gastric, NSCLC |
| Gemtuzumab ozogamicin | Mylotarg | CD33 | Calicheamicin | AML |
| Sacituzumab govitecan | Trodelvy | Trop-2 | SN-38 (irinotecan active metabolite) | TNBC, urothelial carcinoma |
| Enfortumab vedotin | Padcev | Nectin-4 | MMAE | Urothelial carcinoma |
| Polatuzumab vedotin | Polivy | CD79b | MMAE | DLBCL (with bendamustine + rituximab) |
Toxicities / Monitoring
- On-target, off-tumor toxicity (if antigen is expressed on some normal cells).
- Payload-related toxicity:
- Microtubule inhibitors → neuropathy, cytopenias.
- Calicheamicin → hepatotoxicity, VOD.
- Topoisomerase I inhibitors → diarrhea, myelosuppression, interstitial lung disease.
- Infusion-related reactions (due to mAb component).
- Pharmacist role: monitor LFTs, CBC, pulmonary function, manage infusion reactions, assess drug–drug interactions (esp. CYP3A4 metabolism of some payloads).
Summary for Oncology Pharmacists:
ADCs = “guided missiles” in oncology: an antibody directs a highly potent chemotherapy payload specifically to tumor cells, improving efficacy and reducing systemic toxicity. Key drugs include T-DM1, T-DXd, Brentuximab, Inotuzumab, Sacituzumab, Polatuzumab. Pharmacists play a central role in toxicity monitoring and supportive care.
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