Antibody-drug conjugates (ADCs) have established their value as an advanced therapeutic approach to cancer treatment while a novel approach of leveraging immune-cell-engaging multispecific antibodies has begun to show promise. Both types of targeted therapies represent significant innovations in cancer treatment. With distinct mechanisms of action as well as targeting strategies, ADCs, and multispecific antibodies have the potential for synergistic use that may deliver a more powerful approach to cancer therapy.
ADCs: Targeted Delivery of Potent Cytotoxins
ADCs are a form of targeted cancer therapy that combines a monoclonal antibody with a cytotoxic payload. The antibody specifically binds to cancer-associated antigens, delivering the potent drug directly to the tumor cells while minimizing exposure to healthy tissues. ADCs have demonstrated promising results, with objective response rates (ORR) up to 83% [1], depending on the type of cancer and the antigen expression.
Despite these successes, ADCs face several challenges:
- Toxicity: The cytotoxic agents used in ADCs can cause significant off-target effects if released prematurely.
- Resistance: Tumors can develop resistance by downregulating the expression of target antigens or adapting cellular pathways.
- Heterogeneity: Tumors are often heterogeneous, with variable antigen expression, which may limit ADC efficacy.
Multispecific Antibodies: A Broader Targeting Approach
Multispecific antibodies offer a different approach by targeting multiple antigens or engaging various immune system components. These antibodies are designed to address tumor heterogeneity by attacking several cancer-associated markers at once.
Additionally, multispecific antibodies can potentially modulate the immune system, enhancing the body’s natural ability to fight tumors.
Key advantages of multispecific antibodies may include:
- Immune Activation: These therapies are designed to recruit and activate immune cells, which could then potentially drive long-lasting immune responses against the tumor.
- Broader Tumor Targeting: By targeting multiple antigens, multispecific antibodies may overcome the limitations of single-target therapies to reduce tumor escape mechanisms.
- Lower Toxicity: Unlike ADCs, multispecific antibodies do not rely on highly toxic payloads, potentially reducing the risk of side effects.
The Proof on Multispecifics
Recently, preclinical research in Nature Cancer demonstrated the potential of a multispecific approach to augment immune cell activation and achieve more precise tumor targeting and killing.[2] –
In a commentary on this research, Sigrid Ruuls and Paul Parren noted: “In the ongoing search for innovative treatments to combat refractory and relapsed cancer, new preclinical work in multiple myeloma shows that increasing binding avidity by targeting two antigens in one T cell-engaging tri-specific antibody boosts anti-tumor activity and reduces the likelihood of tumor escape relative to current antibody-based therapies.” [3]
Complementary Mechanisms of ADCs and Multispecific Antibodies
Though ADCs and multispecific antibodies have different mechanisms, they may be able to work together to create a more robust anti-cancer response. When combined, these technologies could provide a comprehensive therapeutic approach, targeting cancer through multiple mechanisms and offering the potential for improved patient outcomes.
ADCs are particularly effective in treating “cold” tumors, which are characterized by low immune cell infiltration. These tumors benefit from ADCs because the direct delivery of cytotoxic agents can help shrink the tumor mass, even when the immune system is not fully engaged.
On the other hand, multispecific antibodies may be better suited for treating “hot” tumors, which have higher levels of immune cell infiltration. These therapies are designed to enhance the immune system’s ability to recognize and destroy cancer cells — making them ideal for tumors with active immune environments.
Enhancing Therapeutic Windows
One of the main challenges for ADCs is their narrow therapeutic window due to the toxicity of their payloads. Multispecific antibodies, which have a wider therapeutic window, could be used in combination with ADCs to lower the required ADC dose while maintaining efficacy through immune activation.
This approach could potentially also reduce the risk of side effects from the ADC.
Clinical Synergy: Combining ADCs and Multispecific Antibodies
Recent clinical trials have explored the combination of ADCs with immune checkpoint inhibitors, demonstrating enhanced tumor responses and improved survival outcomes in cancers like HER2-positive breast cancer and triple-negative breast cancer. Similarly, combining ADCs with multispecific antibodies have the potential to amplify the therapeutic effects of both approaches by leveraging their complementary mechanisms.
For example, using ADCs to reduce tumor size followed by treatment with multispecific antibodies have the potential to:
- Induce inflammation: ADCs cause tumor debulking and inflammation, and layering in a multispecific could convert “cold” tumors into “hot” ones.”
- Recruit immune cells: Multispecific antibodies then engage and activate immune cells, boosting anti-tumor immunity and reducing the chance of tumor recurrence.
And while more research is needed, the potential opportunities are intriguing.
The Future of Cancer Treatment
Multispecific antibodies and ADCs each offer unique strengths in cancer treatment. Research and investments on ADCs are flourishing, while multispecifics are on the horizon that overcome the engineering bottlenecks that previously prevented making bispecifics or multispecifics on a large scale.
Multispecific antibodies are currently being studied in clinical trials — with the first T cell-engaging antibody that simultaneously targets BCMA and CD38 on multiple myeloma cells being investigated in a Phase 1 clinical study in relapsed/refractory multiple myeloma.
The future lies in integrating these complementary modalities to develop more effective and personalized cancer therapies. We look forward to seeing what upcoming research unveils.
Reference
[1] Enhertu. National Library of Medicine Daily Medicines. Online. Last accessed on January 20, 2025.
[2] Carretero-Iglesia L, Hall OJ, Berret J, Pais D, Estoppey C, Chimen M, Monney T, Loyau J, Dreyfus C, Macoin J, Perez C, Menon V, Gruber I, Laurendon A, Caro LN, Gudi GS, Matsuura T, van der Graaf PH, Blein S, Mbow ML, Croasdale-Wood R, Srivastava A, Dyson MR, Matthes T, Kaya Z, Edwards CM, Edwards JR, Maiga S, Pellat-Deceunynck C, Touzeau C, Moreau P, Konto C, Drake A, Zhukovsky EA, Perro M, Pihlgren M. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells. Nat Cancer. 2024 Oct;5(10):1494-1514. doi: 10.1038/s43018-024-00821-1. Epub 2024 Sep 11. PMID: 39261676; PMCID: PMC11505469.
[3] Ruuls SR, Parren PWHI. Antibody avidity meets multiple myeloma. Nat Cancer. 2024 Oct;5(10):1452-1454. doi: 10.1038/s43018-024-00805-1. PMID: 39261677.
Featured image: Kateryna Iliznitsova. Licensed under the Unsplash+ License
DOI
