Antibody-Drug Conjugates (ADCs): Precision Therapy for Cancer Treatment
Overview: Antibody-Drug Conjugates (ADCs) represent a groundbreaking approach in cancer treatment, combining the targeting capabilities of antibodies with the potent effects of small molecule cytotoxic drugs. ADCs are complex molecules consisting of three main components: antibodies, linkers, and cytotoxic drugs.
How ADCs Work:
- Targeted Delivery: Antibodies in ADCs specifically bind to antigens present on the surface of tumor cells. This precise targeting facilitates the selective delivery of the cytotoxic drug directly to cancer cells.
- Cytotoxic Action: Once internalized by the tumor cell through endocytosis, the cytotoxic drug is released from the ADC. It then induces cell death by either inserting into DNA or inhibiting microtubule synthesis, leading to apoptosis.
Advantages Over Traditional Chemotherapy:
- Enhanced Specificity: ADCs improve drug delivery specificity by leveraging the antibody’s ability to recognize and bind to tumor-specific antigens. This targeted approach minimizes damage to healthy cells and improves treatment outcomes.
- Effective Potency: The combination of a targeted antibody with a potent cytotoxic drug enhances the therapeutic efficacy against cancer cells.
Development and Challenges:
- Complexity and Barriers: Despite over a century since the concept of ADCs was introduced, only a few have reached the market. The development of ADCs involves overcoming significant technical challenges, including efficient drug-linker attachment and ensuring precise targeting.
- Current Market: As of November 2022, the FDA has approved 13 ADCs, including Lumoxiti (moxetumomab pasudotox-tdfk), which is categorized as an immunotoxin.
The listing of Antibody-drug conjugates(ADCs) Approved by FDA:
| ADC Drug | Trade name | Maker | Disease Indication | Payload/Payload Class | Payload Action | Target | mAb | Linker | DAR | Approval Year |
| Mirvetuximab soravtansine | ELAHERE | ImmunoGen | Platinum-Resistant Ovarian Cancer | Maytansinoid DM4 | Folate receptor alpha | FRα | IgG1 | / | N/A | 2022 |
| Tisotumab vedotin-tftv | Tivdak | Seagen Inc | Recurrent or metastatic cervical cancer | MMAE/auristatin | microtubule inhibitor | Tissue factor | IgG1 | enzyme cleavable | 4 | 2021 |
| Loncastuximab tesirine-lpyl | Zynlonta | ADC Therapeutics | Large B-cell lymphoma | SG3199/PBD dimer | DNA cleavage | CD19 | IgG1 | enzyme cleavable | SG3199/PBD dimer | 2021 |
| Belantamab mafodotin-blmf | Blenrep | GlaxoSmithKline (GSK) | adult patients with relapsed or refractory multiple myeloma | MMAF/auristatin | microtubule inhibitor | BCMA | IgG1 | non-cleavable | 4 | 2020, withdrawn on 22 Nov. 2022 |
| Sacituzumab govitecan | Trodelvy | Immunomedics | adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for patients with relapsed or refractory metastatic disease | SN-38/camptothecin | TOP1 inhibitor | TROP2 | IgG1 | acid cleavable | 7.6 | 2020 |
| Trastuzumab deruxtecan | Enhertu | AstraZeneca/Daiichi Sankyo | adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens | DXd/camptothecin | TOP1 inhibitor | HER2 | IgG1 | enzyme cleavable | 8 | 2019 |
| Enfortumab vedotin | Padcev | Astellas/Seagen Genetics | adult patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor, and a Pt-containing therapy | MMAE/auristatin | microtubule inhibitor | Nectin4 | IgG1 | enzyme cleavable | 3.8 | 2019 |
| Polatuzumab vedotin-piiq | Polivy | Genentech, Roche | relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) | MMAE/auristatin | microtubule inhibitor | CD79 | IgG1 | enzyme cleavable | 3.5 | 2019 |
| Moxetumomab pasudotox | Lumoxiti | Astrazeneca | adults with relapsed or refractory hairy cell leukemia (HCL) | PE38 (Pseudotox) | / | CD22 | IgG1 | Cleavable | N/A | 2018 |
| Inotuzumab ozogamicin | Besponsa | Pfizer/Wyeth | relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia | ozogamicin/calicheamicin | DNA cleavage | CD22 | IgG4 | acid cleavable | 6 | 2017 |
| Trastuzumab emtansine | Kadcyla | Genentech, Roche | HER2-positive metastatic breast cancer (mBC) following treatment with trastuzumab and a maytansinoid | DM1/maytansinoid | microtubule inhibitor | HER2 | IgG1 | non-cleavable | 3.5 | 2013 |
| Brentuximab vedotin | Adcetris | Seagen Genetics, Millennium/Takeda | relapsed HL and relapsed sALCL | MMAE/auristatin | microtubule inhibitor | CD30 | IgG1 | enzyme cleavable | 4 | 2011 |
| Gemtuzumab ozogamicin | Mylotarg | Pfizer/Wyeth | relapsed acute myelogenous leukemia (AML) | ozogamicin/calicheamicin | DNA cleavage | CD33 | IgG4 | acid cleavable | 2–3 | 2017; 2000 |
A stable link between the antibody and the cytotoxic (anti-cancer) agent is a crucial aspect of an ADC conjugation. A highly stable ADC linker will ensure that less of the cytotoxic payload falls off in circulation, driving an improved safety profile, and will also ensure that more of the payload arrives at the cancer cell, driving enhanced efficacy. Linkers are based on chemical motifs including disulfides, hydrazones or peptides (cleavable), or thioethers (noncleavable) and control the distribution and delivery of the cytotoxic agent to the target cell.
AxisPharm develops a broad range of Linkers and provide custom linker synthesis. Our current product catalog covers click chemistry tools such as DBCO, Tetrazine, TCO, BCN and Cycloprpene etc., biotin linkers, PEG linkers, peptide linkers, glucuronide linkers, photo cleavable linkers, Fluorescent Dye probe linkers and folic acid peg linkers. AxisPharm provides the most comprehensive linker and payloads for conjugation research.
As a customer-oriented contract research company, we offer flexible ADC Linker product kits and Bioconjugation services with competitive price.
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