Advancements in antibody-drug conjugates transform cancer therapy

Antibody-drug conjugates (ADCs) have emerged as a promising approach in cancer therapy, offering a 'magic bullet' strategy that combines the precision of monoclonal antibodies with the potency of cytotoxic drugs. The evolution of ADCs has seen significant advancements from first-generation Mylotarg, which was initially approved and later withdrawn due to stability and toxicity issues, to second- and third-generation ADCs that have optimized linker technology and improved stability and efficacy. To date, fifteen ADCs have been approved by regulatory agencies worldwide, with many more in various clinical trial phases, showcasing the rapid progression in this field.

Bispecific ADCs represent a cutting-edge advancement, leveraging bispecific antibodies that can target two distinct antigens or epitopes, enhancing the therapeutic index of ADCs by increasing selectivity and reducing off-tumor toxicity. These bispecific constructs have demonstrated the potential to overcome drug resistance, increase internalization rates, and improve the safety profile of ADCs.

The mechanism of action of bispecific ADCs involves binding to multiple antigens, facilitating receptor clustering and internalization, and releasing cytotoxic payloads within tumor cells, leading to apoptosis. This dual-targeting strategy can also induce a bystander effect, where the released payload affects neighboring tumor cells.

Several bispecific ADCs are in clinical development, targeting a range of cancers with different bispecific antibody designs, linkers, and payloads. For instance, BL-B01D1 targets EGFR and HER3, showing promising results in phase I clinical trials for EGFR TKI-resistant non-small cell lung cancer (NSCLC) patients. REGN5093-M114, another bispecific ADC, targets cMet and has demonstrated efficacy in preclinical models and is currently in clinical trials.

Anti-HER2 bispecific ADCs like ZW49 and MEDI4276 are in clinical trials, showing potential in treating HER2-expressing cancers. M1231, which targets MUC1 and EGFR, has also shown promising results in preclinical models and is in phase I clinical trials for solid tumors.

Strategies to enhance the efficacy of bispecific ADCs include increasing the internalization of ADCs by targeting fast-internalizing receptors, improving selectivity to reduce off-target effects, and overcoming drug resistance by dual-targeting mechanisms. Additionally, improving the half-life and efficacy of ADCs through strategies like the use of albumin-binding domains or small-format antibodies is an area of active research.

Design principles for bispecific ADCs involve careful selection of target antigens, linkers, payloads, and conjugation methods to ensure optimal efficacy and safety. The selection of antigens should consider tumor specificity, internalization potential, and the ability to distinguish between tumor and normal tissues. Linker design should balance stability and release kinetics, while payloads should be potent and have minimal toxic side effects. Conjugation methods must ensure uniformity and stability of the ADC.

The future of bispecific ADCs looks promising, with ongoing clinical trials and continued advancements in design strategies. However, challenges remain in balancing efficacy and safety, and further research is needed to fully realize the potential of this therapeutic class in cancer treatment.