Bispecific-ADC-MCLA-158
A bispecific antibody (BsAb) is a type of engineered antibody that can bind two different antigens or epitopes simultaneously. With its enhanced binding affinity, a bispecific antibody offers greater precision in cancer treatments, such as in antibody-drug conjugates (ADCs). These antibodies are specifically designed to improve therapeutic efficacy by targeting multiple biological markers, particularly in diseases like multiple myeloma and other cancers.
Key Benefits of Bispecific Antibodies:
- Dual Targeting: BsAbs bind to two antigens, increasing precision in attacking cancer and immune cells.
- Immune Activation: BsAbs bring immune cells like T cells closer to cancer cells, boosting the immune response.
- Improved Efficacy: Targeting two markers enhances treatment selectivity and lowers the risk of off-target effects.
BsAbs in ADCs (Antibody-Drug Conjugates):
ADCs are targeted cancer therapies that link antibodies to cytotoxic drugs. The antibody directs the drug to specific cancer markers, minimizing harm to healthy cells.
When combined with BsAbs, ADCs provide extra advantages:
- Precision Targeting: BsAbs improve specificity by binding two antigens, lowering resistance risks by addressing two pathways.
- Better Drug Delivery: BsAbs enhance internalization of the ADC into cancer cells by engaging two receptors, increasing payload delivery.
- Stronger Cell Killing: BsAbs can simultaneously bind a tumor marker and immune cell receptor, bringing immune cells to the tumor while delivering the drug for better tumor destruction.
Advantages of BsAbs in ADCs:
- Higher Specificity: Targeting two antigens makes treatment more precise.
- Reduced Drug Resistance: Targeting two pathways helps prevent tumor escape.
- Dual Action: BsAbs engage immune cells and deliver cytotoxic drugs, maximizing therapeutic effects.
Applications in Cancer Therapy:
- Solid Tumors: BsAbs improve ADCs for solid tumors by addressing complex antigen expression.
- Blood Cancers: BsAb-ADCs enhance immune cell recruitment and drug delivery to tumor cells in blood cancers.
Real-World Example: MCLA-158 in ADC Development
MCLA-158, developed by Merus NV, is a bispecific antibody that targets EGFR and LGR5. These markers are key in cancer growth, making MCLA-158 effective for solid tumors like colorectal cancer and head and neck squamous cell carcinoma (HNSCC).
- Dual Targeting: MCLA-158 binds to EGFR (common in many cancers) and LGR5 (a cancer stem cell marker). This dual approach attacks both tumor cells and cancer stem cells.
- Use in ADCs: In studies, MCLA-158 was paired with cytotoxic drugs, such as MMAE to create an ADC. This combination delivers the drug directly to cells expressing EGFR and LGR5, boosting precision and sparing healthy cells.
- Clinical Progress: MCLA-158 is in clinical trials for metastatic colorectal cancer and HNSCC, showing promise in cases resistant to EGFR therapies.
Advantages of MCLA-158 in ADCs:
- Enhanced Specificity: Binding both EGFR and LGR5 improves ADC specificity, reducing off-target effects.
- Overcomes Resistance: Dual targeting lowers the risk of cancer cells developing resistance.
- Better Tumor Killing: Targeting tumor and cancer stem cells leads to stronger drug delivery and better patient outcomes.
Broader Applications:
- Solid Tumors: Bispecific ADCs like MCLA-158 address complex tumor antigen expressions.
- Blood Cancers: BsAb-ADCs are also effective in improving drug delivery in blood cancers.
Conclusion:
MCLA-158 highlights how bispecific antibodies enhance ADCs in cancer therapy. By targeting both tumor cells and cancer stem cells, it shows the strength of dual-targeting strategies in treating tough cancers like colorectal cancer. Combining BsAbs with ADCs improves precision, reduces resistance, and enhances treatment outcomes.
Ref:
Herpers, B., Eppink, B., James, M.I. et al. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. Nat Cancer 3, 418–436 (2022).