The ABC of ADCs: Antibody-Drug Conjugates Explained Simply

Antibody-drug conjugates (ADCs) represent a cutting-edge approach in cancer therapy, combining the precision of antibodies with the potency of cytotoxic drugs. This innovative class of biopharmaceuticals has gained significant traction in recent years, offering new hope for patients with various types of cancer.

Today marks a significant milestone with the PBS decision to reimburse an ADC for HER-2 positive breast cancer that redefines the traditional threshold of HER-2 expression required for efficacy. This breakthrough expands access for patients who previously did not meet the criteria for HER-2 directed therapies, demonstrating how ADCs can push the boundaries of targeted cancer treatment and challenge our thinking - it is turning science fiction into science fact.

The ABCs of ADC Design - lets get simple.

A is for Antibody: The antibody is the targeting component of an ADC. It must be highly specific to an antigen (a protein) that is abundantly expressed on cancer cells but minimally present on healthy cells. The antibody should also be capable of being internalized (taking from the outside to the inside) by the cancer cell after binding. Recent advances have focused on optimising antibody selection and engineering to improve targeting, internalization rates, and overall ADC stability.

B is for Binder (Linker): The linker is a critical component that connects the antibody to the drug payload. It must be stable in circulation to prevent premature drug release but able to release the drug once inside cancer cells. Linkers can be classified as:

• Cleavable: These contain chemical triggers that allow for drug release under specific conditions (e.g., low pH or presence of certain enzymes).
• Non-cleavable: These rely on complete degradation of the antibody within the cell to release the drug.
• This has been the 'missing link(er)' in getting ADC's right since their early use in the late 90's

Recent research has focused on developing linkers that optimise the drug-to-antibody ratio (DAR) and improve ADC stability and efficacy - this is important, some ADC's have ratios of 8 payload molecules to 1 antibody (1:8).

C is for Cytotoxic Payload: The payload is typically a highly potent cytotoxic agent that would be too toxic for systemic administration on its own. Common payloads include microtubule inhibitors, DNA-damaging agents, and topoisomerase inhibitors. Recent trends show a diversification of payload types, including the exploration of immunomodulatory agents to enhance anti-tumor immune responses.

How ADCs Work: The Mechanism of Action

The mode of action of ADCs involves several steps, each crucial for their effectiveness:

1. Targeting: The antibody component of the ADC circulates in the bloodstream until it finds and binds to specific antigens (a protein) on the surface of cancer cells.
2. Internalization: Once bound, the ADC-antigen complex is internalized by the cancer cell through a process called receptor-mediated endocytosis - it goes from docking to the cell into the cell
3. Drug Release: Inside the cell, the ADC enters lysosomes—cellular compartments with an acidic environment. Here, the linker is broken down, releasing the cytotoxic drug.
4. Cell Death: The released drug interferes with critical cellular processes, such as DNA replication or microtubule function (cells need these), leading to cancer cell death.
5. Bystander Effect: In some cases, the released drug can also affect nearby cancer cells, enhancing the overall therapeutic effect.

This mechanism allows ADCs to deliver a concentrated dose of cytotoxic agents directly to cancer cells, potentially improving efficacy while reducing systemic side effects compared to traditional chemotherapy - think of it like a trojan horse.

Current State of ADC Development

As of 2024, the field of ADCs has seen significant progress:

1. Approved ADCs: By the end of 2020, nine ADCs had received FDA approval for various cancer indications. This number has since increased, with 14 approved ADCs reported in more recent literature.
2. Clinical Trials: Numerous ADCs are in various stages of clinical development, targeting a wide range of cancer types.
3. Technological Advancements: Ongoing research focuses on improving each component of ADCs, including novel antibody engineering techniques, more stable and efficient linkers, and diverse payload options.
4. Expanded Applications: While initially focused on hematological malignancies, ADCs are now being developed for solid tumors and even non-oncological conditions.

Evidence Base and Future Directions

The efficacy of ADCs has been demonstrated in numerous clinical trials, leading to FDA approvals for various cancer types. However, challenges remain, including off-target toxicity, resistance mechanisms, and manufacturing complexity. Future research directions include identifying novel cancer-specific antigens, developing new payloads, designing linkers that balance stability with efficient payload release, exploring combination therapies with other cancer treatments, and improving analytical methods for ADC characterization.

ADCs represent a promising and rapidly evolving field in cancer therapy. By combining the specificity of antibodies with the potency of cytotoxic drugs, ADCs offer a targeted approach that continues to show promise in clinical settings. As research progresses, we can expect further refinements in ADC design and expanded therapeutic applications, potentially revolutionizing cancer treatment in the coming years.

At MedWise, we make complex science simple. Translating science and empowering minds

Just as ADCs target cancer cells with precision, MedWise is dedicated to translating intricate scientific advances into clear, impactful insights. Our expertise spans three core areas:

1. Medical Affairs: Bridging science with practice to inform clinical decisions.
2. Patient Affairs: Ensuring patient voices shape research and treatment strategies and that patients and carers comprehend as much as they can
3. Medical Affairs Learning, Development, and Capabilities: Empowering medical teams with the knowledge and skills needed to excel and helping modernise medical affairs departments

Through these pillars, we help turn cutting-edge therapies like ADCs into real-world successes, making sure that the science behind them is not just understood, but effectively communicated and implemented to all stakeholders, especially patients. MedWise Consulting .

https://medwise.com.au/#contact-us - we would love to talk you so reach out.

References:

IQ Biosciences (n.d.) ‘The ABCs of ADCs: An Introduction to Antibody-drug Conjugates’, IQ Biosciences. Available at: https://iqbiosciences.com/blog/the-abcs-of-adcs-an-introduction-to-antibody-drug-conjugates/ (Accessed: 1 September 2024).

Nature Communications (2022) ‘Antibody-Drug Conjugates: The Biological Missile for Targeted Cancer Therapy’, Nature Communications. Available at: https://www.nature.com/articles/s41392-022-00947-7 (Accessed: 1 September 2024).

Journal of Clinical Oncology (2023) ‘Clinical Applications of Antibody-Drug Conjugates in Oncology’, Journal of Clinical Oncology. Available at: https://ascopubs.org/journal/jco (Accessed: 1 September 2024).