Despite advances in anticancer chemotherapy, small-molecule anticancer drugs are associated with a narrow therapeutic window and limited efficacy. A robust strategy for targeted therapy, known as antibody-drug conjugates (ADCs), has been developed to counterfeit this challenge.
What are antibody–drug conjugates?
ADCs consist of a tumor-specific monoclonal antibody covalently conjugated to a cytotoxic drug using a chemical linker. The cytotoxic drugs (chemotherapeutic agents) linked to the monoclonal antibody are known as cytotoxic payloads or warheads.
ADCs increase the efficacy and reduce the systemic toxicity associated with current chemotherapeutic regimens. ADCs can deliver highly cytotoxic payloads directly to tumor cells, and hence they are highly lethal towards the targeted tumor cells. Due to this selectivity, ADCs are also referred to as the "Trojan Horses."
How do antibody-drug conjugates work?
ADCs use monoclonal antibodies to deliver potent cytotoxic payloads to tumors that overexpress a particular target.
To enable exclusive binding of the monoclonal antibodies (mAb) to its target site, the target antigens should be expressed on the tumor cells but not on normal cells.
Once the ADC recognizes and attaches to its target antigen, the ADC–antigen complex is internalized into the cell through receptor-mediated endocytosis. The ADCs are engulfed into endosomes that eventually mature and fuse with lysosomes.
Due to the acidic environment and the presence of lysosomal proteases such as cathepsin B, the ADC is cleaved and the cytotoxic drug is released into the cytoplasm of tumor cells. Once released, the cytotoxic warheads bind to their target, either the microtubules or DNA, and induce apoptosis, and ultimately cell death.
Key Requirements of ADCs
The success of an ADC is depends significantly on the specific properties of its four components – antibody, antigen, cytotoxic payload and the linker.
Target antigen selection
Selecting a unique antigenic target for the monoclonal antibody is the most critical step during ADC development. The antigen should be selectively expressed in tumor cells and have a negligible expression in the healthy cell. The unique antigenic target should also have robust internalization properties to promote the transport of ADC into the cell, which, in turn, will increase the efficacy of the cytotoxic agent.
Selection of antibody moiety
Another vital component is the antibody. Apart from delivering the cytotoxic drug to the tumor cell, the antibody should possess high binding affinity for the tumor cells' antigens. Low immunogenicity, low cross-reactivity, good retention, and adequate linkage-binding capacity are other ideal properties.
Linkers link the cytotoxic drug to the monoclonal antibody
The linkers also play a vital role. When the ADC complex is released in the systemic circulation, the linker should remain stable and prevent the release of the cytotoxic payload in the off-target tissue. The linker must keep the ADC in an inactive, nontoxic state; however, upon internalization, the linker should release the cytotoxic drug.
Cytotoxic payloads
The cytotoxic payloads are activated when they are released inside the tumor cell cytoplasm. The drug should be highly potent and have a small molecular weight. They should possess high stability in the systemic circulation and lysosomes. Low immunogenicity and a long half-life are other essential features of an ideal cytotoxic payload. Moreover, the cytotoxic payload's chemistry should be such that it can be easily conjugated to the linker while retaining the internalization property of the monoclonal antibody.
DNA-damaging agents (Calicheamicin, Doxorubicin) and microtubule-disrupting agents (Auristatin, Maytansinoids) are the two common classes of cytotoxic payload used in ADC development.
Antibody-drug conjugates in clinical development
The concept of ADCs may seem pretty straightforward; however, developing an optimized and functional ADC is challenging. Optimizing the formula to balance the three components right is the main issue.
Though many ADC therapies are in the pi...
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