Mechanisms of Bispecific Antibodies

Bispecific antibodies (BsAbs) are artificial antibodies that can simultaneously bind to two different antigens or epitopes, thereby enabling novel functionalities and improved efficacy compared to conventional monoclonal antibodies (mAbs) that can only bind to one antigen or epitope. BsAbs are not naturally occurring, but rather engineered by various methods, such as chemical conjugation, genetic fusion, or hybrid hybridoma. BsAbs have shown great potential for the treatment of various diseases, especially cancers, by exploiting their unique mechanisms, such as dual-targeting, cross-linking, blocking, and modulating. However, BsAbs also face significant challenges, such as complex engineering and manufacturing, reduced stability and solubility, and increased immunogenicity and toxicity. Therefore, it is important to understand the mechanisms of BsAbs and how they differ from mAbs, in order to optimize their design and application.

Inherent Mechanisms of Monoclonal Antibodies

Monoclonal antibodies (mAbs) are antibodies that are produced by a single clone of B cells and have identical specificity for a single antigen or epitope. mAbs can recognize and bind to their target antigens with high affinity and specificity and exert their therapeutic effects through various mechanisms, such as:
- Antigen recognition: mAbs can directly inhibit the function of their target antigens, such as receptors, ligands, enzymes, or toxins, by blocking their binding, activation, or catalysis.
- Effector functions: mAbs can recruit the immune system to eliminate their target antigens by activating the complement system, inducing antibody-dependent cellular cytotoxicity (ADCC), or triggering antibody-dependent cellular phagocytosis (ADCP).
- Pharmacokinetics: mAbs can modulate the distribution and clearance of their target antigens by altering their solubility, stability, and accessibility.

mAbs have revolutionized the field of biotechnology and medicine and have been widely used for the diagnosis, prevention, and treatment of various diseases, especially cancers. However, mAbs also have some limitations and drawbacks, such as low potency, poor penetration, and drug resistance. Therefore, there is a need to develop novel antibody-based therapeutics that can overcome the limitations and drawbacks of mAbs and enhance their therapeutic potential. One of the most promising strategies is to engineer BsAbs that can simultaneously bind to two different antigens or epitopes, thereby enabling novel functionalities and improved efficacy compared to mAbs.

Specific Mechanisms of Bispecific Antibodies

Bispecific antibodies (BsAbs) are engineered antibodies that can simultaneously bind to two different antigens or epitopes, thereby enabling novel functionalities and improved efficacy compared to mAbs that can only bind to one antigen or epitope. BsAbs are not naturally occurring but rather created by various methods, such as chemical conjugation, genetic fusion, or hybrid hybridoma. BsAbs can be classified into different types and categories based on their structure, format, valency, and specificity.
BsAbs can exploit their unique structure, format, valency, and specificity to exert their therapeutic effects through various mechanisms, such as: 
- Dual-targeting: BsAbs can simultaneously target two different antigens or epitopes and achieve synergistic or additive effects by enhancing the potency, specificity, or diversity of antigen recognition. 
- Cross-linking: BsAbs can cross-link two different antigens or epitopes and induce the proximity or interaction of two different cells or molecules by bridging the gap, facilitating contact, or triggering aggregation. 
- Blocking: BsAbs can block the function of two different antigens or epitopes and prevent their binding, activation, or catalysis by competing, interfering, or neutralizing. 
- Modulating: BsAbs can modulate the function of two different antigens or epitopes and enhance or reduce their expression, signaling, or activity by stimulating, inhibiting, or regulating.

BsAbs have shown great potential for the treatment of various diseases, especially cancers, by exploiting their unique mechanisms

References

1. Labrijn AF, et al. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019 Aug;18(8):585-608.
2. Spiess C, et al. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 2015 Oct;67(2 Pt A):95-106.
3. Kontermann RE. Dual targeting strategies with bispecific antibodies. MAbs. 2017 Jan;9(1):47-56.
4. Brinkmann U, et al. The development of immunoconjugates for targeted cancer therapy. Nat Rev Clin Oncol. 2008 Oct;5(10):597-606.
5. Fan G, et al. Bispecific antibodies and their applications. J Hematol Oncol. 2015 Dec 29;8:130.
6. Wu C, et al. Advances in engineering the Fc region of bispecific antibodies. Biomed Res Int. 2015;2015:620543.