From Monoclonal to Multispecific: Why Are More Complex Antibodies Needed?

mAbs have achieved significant success in treating diseases like cancer and autoimmune disorders. However, their effectiveness in complex diseases has been limited due to their single-target mechanism of action. For example, in the tumor microenvironment, cancer cells often evade immune detection through multiple mechanisms, making it difficult for a single antibody to provide a comprehensive anti-tumor effect. To overcome this, researchers have developed bispecific antibodies (BsAbs), which integrate two antigen-binding sites within a single molecule to enhance anti-tumor activity. With advancements in technology, antibody drugs have evolved to target three or more antigens simultaneously, leading to the development of MsAbs, including trispecific antibodies (TsAbs) and tetraspecific antibodies (TetraMabs), which hold great promise in cancer treatment.

https://doi.org/10.1038/s41586-020-2168-1

Four Transformative Waves Have Shaped Development of the Biopharmaceutical Industry

Mechanism of Action of MsAbs: How to Achieve "One Arrow, Multiple Targets"?

• BsAbs: Dual Attack, Precise Killing

BsAbs enhance targeting ability and improve therapeutic efficacy by simultaneously binding two different targets. One of the most common designs is the CD3×TAA (tumor-associated antigen) T-cell engager (TCE), which directly recruits T-cells to the tumor microenvironment, activating them to release cytotoxic factors that kill the tumor, such as Blincyto (CD3×CD19). Another strategy is dual TAA targeting, which improves tumor specificity by recognizing two tumor antigens, thereby reducing the risk of resistance caused by antigen loss, such as Zanidatamab (HER2×HER2). In addition, some BsAbs combine tumor antigens with immune checkpoints, such as CD47×PD-L1, which offers both antitumor and immunoregulatory effects.

https://doi.org/10.1038/s41416-020-01225-5

Mechanism of CD3 BsAbs-mediated T-cell redirection in cancer.

• TsAbs: Multidimensional Synergy, Overcoming Resistance

TsAbs build upon the BsAbs design by adding a third target to enhance immune effects or overcome resistance. Some TsAbs combine CD3 with two different TAAs to improve tumor specificity and reduce the risk of antigen loss. For example, SIM0500, developed by Simcere Pharmaceutical, targets GPRC5D, BCMA, and CD3, effectively killing multiple myeloma cells, overcoming resistance, and maintaining long-term tumor suppression. Another strategy is the introduction of costimulatory receptors, such as SAR442257 (CD38/CD3/CD28) developed by Sanofi. This antibody mediates T-cell killing of CD38-positive tumors through CD3 and enhances T-cell activation via the CD28 costimulatory signal. Additionally, to extend the half-life, Numab Therapeutics AG developed NM32-2668, an antibody targeting ROR1, CD3, and human serum albumin (HSA). This antibody redirects T-cells to attack ROR1-positive tumors while extending circulation time through its HSA-binding domain, optimizing the dosing regimen.

https://doi.org/10.1038/d41586-019-03495-3

TsAbs Targeting CD38/CD3/CD28

• TetraMAbs: Comprehensive Regulation, Expanding Immune Killing Potential

TetraMAbs further break through targeting limitations, enabling a more comprehensive anti-tumor regulation strategy. For example, Biokin Pharmaceutical has developed several TetraMAbs, including GNC-038 (CD3×4-1BB×PD-L1×CD19), which amplifies anti-tumor immune effects through a quadruple mechanism: T-cell activation, costimulation enhancement, immune checkpoint blockade, and tumor-specific targeting. This multidimensional regulation not only improves efficacy but also reduces the risk of tumor immune escape, providing a more powerful tool for cancer immunotherapy.

Source: Biokin Pharmaceutical Official Website

Some of Biokin Pharmaceutical's Pipelines

Conclusion

From mAbs to MsAbs, the development of antibody drugs has greatly enhanced the precision and efficacy of cancer immunotherapy. BsAbs strengthen tumor-killing ability through a dual-target mechanism, TsAbs further optimize immune effects and overcome resistance, while TetraMAbs expand immune killing potential through comprehensive regulation. These innovative strategies not only improve the efficacy of antibody drugs but also provide more promising solutions for cancer treatment. With ongoing advancements in antibody engineering technology, MsAbs are expected to play an even greater clinical role in the future.

ACROBiosystems offers high-quality CD3 proteins, including CD3E&CD3D, CD3E&CD3G, CD3E, CD3D, and CD3G. CD3E&CD3D and CD3E&CD3G have been verified as a 1:1 heterodimer by nonreductive electrophoresis and MALS. Additionally, CD3 proteins have been extensively tested for binding activity with various TCEs (e.g., CD3×BCMA, CD3×DLL3) and clinical-stage bispecific antibodies (e.g., OKT3, SP34-2, UCHT1), supporting antibody drug screening and optimization.

Molecule list

>> Learn More About Our Multispecific Antibody Targets and Services

Reference

1. Deshaies R J. Multispecific drugs herald a new era of biopharmaceutical innovation[J]. Nature, 2020, 580(7803): 329-338. https://doi.org/10.1038/s41586-020-2168-1

2. Singh A, Dees S, Grewal I S. Overcoming the challenges associated with CD3+ T-cell redirection in cancer[J]. British journal of cancer, 2021, 124(6): 1037-1048. https://doi.org/10.1038/s41416-020-01225-5

3. Garfall A L, June C H. Trispecific antibodies offer a third way forward for anticancer immunotherapy[J]. 2019. https://doi.org/10.1038/d41586-019-03495-3

4. Goebeler M E, Stuhler G, Bargou R. Bispecific and multispecific antibodies in oncology: opportunities and challenges[J]. Nature Reviews Clinical Oncology, 2024, 21(7): 539-560. https://doi.org/10.1038/s41571-024-00905-y