Antibody-Drug Conjugate (ADC) Therapy

Antibody-Drug Conjugates (ADCs) represent a targeted cancer treatment strategy that combines the specificity of monoclonal antibodies with the potency of cytotoxic drugs. ADCs are designed to deliver the drug directly to cancer cells while minimizing effects on healthy tissues, reducing systemic toxicity compared to conventional chemotherapy.

How ADCs Work

1. Antibody: Targets specific antigens (proteins) that are overexpressed on cancer cells.
2. Drug (Payload): A highly potent cytotoxic agent, often lethal at picomolar concentrations.
3. Linker: Connects the antibody to the drug and ensures the payload is released at the cancer site. Stable in circulation, the linker breaks down in the target environment, releasing the drug.

The ADC binds to the antigen on the cancer cell surface, gets internalized into the cell, and releases the cytotoxic payload, leading to cancer cell death.

ADC Therapies in Use

Here are some prominent ADCs approved for clinical use, along with their indications:

Cancers Treated with ADCs

ADCs have been approved or are under investigation for various cancers:

• Breast Cancer: HER2-positive and triple-negative types.
• Lymphomas: Hodgkin lymphoma and non-Hodgkin lymphomas.
• Leukemias: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
• Bladder and Urothelial Cancers.
• Ovarian Cancer.
• Lung Cancer: Investigational ADCs target EGFR and HER3 in lung cancers.

Advantages of ADC Therapy

1. Targeted Approach: Precision delivery minimizes systemic toxicity.
2. Improved Efficacy: The cytotoxic payloads are extremely potent and can kill cells resistant to traditional chemotherapies.
3. Combination Potential: ADCs can be combined with immunotherapies or other targeted agents.

Challenges and Limitations

1. Resistance: Tumor cells may downregulate target antigens or efflux the cytotoxic agent.
2. Toxicity: Despite specificity, off-target effects can occur due to antigen expression in normal tissues.
3. Cost: ADCs are expensive and may not be accessible to all patients.

Increasing the payload in Antibody-Drug Conjugates (ADCs) involves optimizing the drug-to-antibody ratio (DAR) and designing ADCs that can effectively deliver more cytotoxic agents to cancer cells. The strategies include advancements in antibody engineering, linker technology, and conjugation methods. Here’s how payload delivery is enhanced:

1. Increasing Drug-to-Antibody Ratio (DAR)

• The DAR is the average number of cytotoxic drug molecules attached to each monoclonal antibody.
• Typically, a DAR of 2-4 is common for stability and efficacy, but advances aim to increase DAR without compromising functionality.

Techniques include:

• Site-specific conjugation: Ensures precise attachment points, avoiding random coupling, which can destabilize the ADC or affect its targeting ability.
• Engineering antibodies with multiple conjugation sites to hold more payloads.

2. Using Highly Potent Payloads

• Payloads are becoming more potent, allowing even small amounts to have significant anti-cancer effects.
• Advances in cytotoxic drug chemistry produce agents with higher potency, which means fewer drug molecules are needed to achieve therapeutic effects.

Examples:

• MMAE (monomethyl auristatin E): A potent microtubule inhibitor.
• Calicheamicin: A DNA-damaging agent.

3. Dual-Payload ADCs

• Dual payloads combine two different cytotoxic drugs in one ADC to target cancer cells via complementary mechanisms.
• This approach increases the likelihood of overcoming resistance while delivering a higher overall payload.

4. Multivalent Antibodies

• Multivalent or bispecific antibodies can bind to two or more targets simultaneously, allowing for better tumor targeting and potentially enabling more payloads per molecule.

5. Optimizing Linker Technology

• Improved linker stability prevents premature release of the payload in circulation.
• Smart linkers can release more payload in the tumor environment, such as:
• pH-sensitive linkers: Release drugs in acidic tumor microenvironments.
• Enzyme-cleavable linkers: Respond to tumor-specific enzymes.

6. Polymer Conjugation

• Attaching polymer scaffolds to antibodies allows multiple payloads to be linked, significantly increasing the DAR while maintaining functionality.

Polymeric ADCs hold potential for higher payload capacity with controlled release.

Challenges of Increasing Payload

1. Stability Issues: High DAR can destabilize the ADC, leading to premature drug release.
2. Altered Pharmacokinetics: Increased payloads might affect how the ADC circulates and binds to its target.
3. Toxicity Concerns: Delivering too many payloads could harm healthy tissues, especially if the target antigen is also expressed at low levels in normal cells.

Examples of ADC Payload Innovations

1. Trastuzumab Deruxtecan (Enhertu): High DAR (average ~8) and uses a cleavable linker to release potent topoisomerase inhibitors.
2. Polatuzumab Vedotin (Polivy): Targets CD79b with MMAE as a payload.

By carefully balancing DAR, linker design, and antibody specificity, ADC technologies continue to evolve, offering higher payloads while maintaining precision and minimizing systemic toxicity.