ADCs and their Drug Development Process

Q1 - Can you describe the current landscape of ADCs in terms of their therapeutic potential and market impact?

Antibody-drug conjugates (ADCs) have made great progress in recent years, targeting more than 260 recognized antigens today. The landscape is becoming more diverse, beyond conventional antibody-based conjugates to peptide-drug conjugates, radio conjugates, and other cutting-edge modalities. This scientific and commercial promise is reflected in the more than a dozen ADCs that have already received US approval. Leading the effort are Daichi Sankyo and AstraZeneca with Enhertu, sales of which hit $1.6 billion in 2022, and, based on current projections, are expected to reach an astounding $9 billion by 2028. By utilizing these changing development methodologies, it is anticipated that the ADC industry, with its immense potential, will grow to around $30 billion by 2028.

Q2 - What are the primary challenges faced during the development of ADCs, especially regarding efficacy, safety, and manufacturing scalability?

Developing ADCs is a complex endeavour where precision medicine intersects with advanced drug delivery systems. During development, one must select the most suitable target antigens for the specific ADC—those primarily expressed on the intended tumour cells—to prevent cross-reactivity with healthy cells. The precision of the ADC also comes from the expertly engineered linker, which allows the antibodies in the compound to be released at the site of the tumour and not before. The drug-to-antibody ratio (DAR) is crucial to ensuring ADC performance.

Regarding safety, the specificity of the ADC is of the utmost importance to minimize toxicity to non-cancerous cells. One must constantly calibrate the therapeutic window and determine the proper dosing requirements through rigorous clinical studies. Additionally, there is always the potential for immunogenicity—the immune system can recognize and react against the ADC, which can limit its effectiveness and pose safety risks.

The manufacturing stage demands high precision to ensure each batch is consistent, especially when upgrading production. Quality control becomes more challenging as the scale increases, and all components of the ADC need to be tested and observed, from the DAR to the purity of the product. The components of ADCs often require specialized handling and storage, which can get more logistically complicated as volume increases. The process is like a symphony of finely tuned instruments—all must work harmoniously to afford the best patient benefits.

Q3 - How do you approach selecting antibody targets and cytotoxic payloads to optimize ADC effectiveness?

When developing ADCs, choosing the antibody target and the cytotoxic payload is pivotal for ensuring therapeutic effectiveness while minimizing risks. The ideal antibody target, an antigen, is predominantly expressed on tumour cells, minimizing exposure to healthy cells and enhancing the delivery precision of the cytotoxic payload. Such target antigens should be readily externalizable upon ADC binding, allowing the entry of the cytotoxic agent into the cancer cell. These targets must also be accessible and not obscured by the tumour microenvironment. They are essential to the survival or proliferation of cancer cells, making them the most effective point of attack.

The cytotoxic payload must be highly potent, allowing maximum efficacy at lower doses and reducing potential side effects. The payload's mechanism should be chosen for its action on the targeted cancer. Integrating the payload with the antibody via the linker is also crucial; the linker must stabilize the bond in the bloodstream and allow for the timely release of the payload inside the target cell. Key factors such as the DAR require optimization to balance effective drug delivery with maintaining the antibody’s functionality. Additionally, the linker’s design must ensure that the ADC remains stable until reaching the target site. Finally, the scalability of the manufacturing process is essential to transition ADCs from the lab to commercial production, encompassing every stage from antibody production and payload-linking to purification, ensuring a steady supply for clinical use.

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