Antibody-Drug Conjugates (ADCs) represent a targeted approach in cancer therapy, combining the specificity of antibodies with the potency of chemotherapy. These drugs are designed to deliver a therapeutic agent directly to cancer cells while minimizing harm to healthy tissues. The active drug component within an ADC is known as the payload, and its ability to effectively kill cancer cells is central to the therapy’s success.
Defining ADC Payloads
An ADC payload is the cytotoxic, or cell-killing, agent chemically attached to a monoclonal antibody. This payload functions as a potent pharmaceutical molecule, often too toxic for systemic use on its own, meaning it would cause unacceptable side effects if given widely throughout the body. The antibody component of the ADC acts as a precise delivery vehicle, guiding the payload directly to cancer cells that express specific target proteins on their surface.
Once the ADC binds to its target on the cancer cell, the entire complex is internalized through a process called receptor-mediated endocytosis. Inside the cell, the ADC undergoes degradation within lysosomes, cellular compartments containing enzymes and an acidic environment. This degradation process triggers the release of the active payload, allowing it to exert its cell-killing effects.
Mechanisms of Action
Once released inside the cancer cell, ADC payloads execute their cell-killing function by disrupting fundamental cellular processes. A common mechanism involves damaging DNA, which is the genetic material essential for cell function and replication. Payloads can achieve this through various means, such as creating cross-links within DNA strands or inducing DNA strand breaks, which are irreparable forms of damage.
Another significant mechanism of action for payloads is the disruption of microtubules. Microtubules are protein structures that form part of the cell’s cytoskeleton and are involved in many cellular processes, including cell division. Payloads can interfere with microtubule formation (polymerization) or breakdown (depolymerization), preventing the cell from properly dividing. This interference leads to cell cycle arrest, typically in the G2-M phase, and ultimately triggers programmed cell death, known as apoptosis, in the cancer cell.
Common Payload Classes
The cytotoxic drugs used as ADC payloads fall into classes based on their cellular targets and mechanisms. One class is tubulin inhibitors, which interfere with the dynamics of microtubules, structures necessary for cell division. These inhibitors either prevent the assembly of tubulin into microtubules or block their disassembly. Examples include auristatins like Monomethyl Auristatin E (MMAE) and Monomethyl Auristatin F (MMAF), and maytansinoids such as DM1 and DM4.
Another class comprises DNA damaging agents, which directly target the cancer cell’s genetic material. These payloads work by introducing irreparable damage to DNA, such as cross-linking DNA strands or causing strand breaks. Examples of DNA damaging agents used as ADC payloads include calicheamicins and pyrrolobenzodiazepines (PBDs).
Key Considerations for Payload Design
Designing an effective ADC payload involves several considerations to ensure both potency and safety. Payloads must exhibit cytotoxicity, meaning they can kill cancer cells at very low concentrations, often in the picomolar (0.001 nM) to nanomolar (1 nM) range. This potency is important because only a limited amount of the payload is delivered to each cancer cell. The payload must also maintain stability while circulating in the bloodstream to prevent premature release, ensuring it reaches the tumor intact.
The linker chemistry, which connects the payload to the antibody, is also a design factor. The linker must be stable in circulation but capable of efficient and precise release of the payload once inside the target cancer cell. This release can be triggered by specific conditions within the cell, such as enzymatic activity or acidic environments. Some payloads can exhibit a “bystander effect,” where the released payload diffuses out of the targeted cell to kill nearby cancer cells that may have lower antigen expression, which can be an advantage in treating heterogeneous tumors.