Surreal illustration of a bispecific antibody targeting a cancer cell and an immune cell.

Bispecific Antibodies: The Next Frontier in Targeted Therapies?

Kai Mendoza in Science & Nature August 2025 • 4 min read.

"How asymmetric engineering is revolutionizing bispecific antibody design for enhanced precision and reduced side effects."

Therapeutic antibodies have become essential tools in treating various diseases. These antibodies often rely on their Fc region to trigger effector functions, which involve the immune system attacking diseased cells. These effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), are activated when the antibody interacts with immune cells and complement proteins.

Bispecific antibodies represent an innovative class of therapeutics designed to recognize two different targets simultaneously. This dual-targeting approach allows for novel functions that traditional antibodies cannot achieve. However, many therapeutic strategies require these bispecific antibodies to have reduced or silenced effector functions. This is particularly important when the antibody redirects immune cells or engages immunomodulatory targets, where uncontrolled effector activity can lead to unintended side effects.

Traditional methods for reducing effector function have relied on specific antibody subtypes or symmetric mutations in the Fc region. Now, researchers are exploring asymmetric Fc engineering to fine-tune the activity of bispecific antibodies. This involves introducing different mutations on each arm of the Fc region, offering greater control over effector functions and improving the antibody's overall therapeutic profile.

Asymmetric Fc Engineering: A New Approach

Surreal illustration of a bispecific antibody targeting a cancer cell and an immune cell.

A recent study published in Antibodies journal details a novel approach to engineering asymmetric Fc regions in bispecific antibodies. Researchers at Zymeworks Inc. and the National Research Council Canada developed asymmetric Fc mutations that reduce or silence effector functions. This innovative design involves introducing charged mutations in the lower hinge and CH2 domain of the Fc region, creating heterodimeric molecules with distinct properties.

The researchers designed several asymmetric Fc variants and assessed their binding to Fc gamma receptors (FcyRs) and C1q, a protein involved in the complement pathway. Surface plasmon resonance (SPR) experiments showed that the designed mutations significantly reduced binding to all FcyRs and C1q. This indicates that these asymmetric mutations effectively minimize the antibody's ability to activate immune responses through these pathways. Furthermore, ex vivo ADCC and CDC assays confirmed a consistent reduction in effector activity, demonstrating the functional impact of the engineered mutations.

Key findings from the study include: Reduced binding to FcyRs and C1q. Consistent reduction in ADCC and CDC activity. Increased thermal stability for some designs. Improved purification strategy using ion exchange chromatography.

One notable advantage of this asymmetric approach is the ability to separate homodimeric impurities using ion exchange chromatography. The introduction of charged mutations creates differences in the isoelectric point (pI) of the heterodimeric antibody and its homodimeric counterparts. This allows for efficient separation and purification, which is crucial for producing high-quality bispecific antibodies suitable for therapeutic use. Differential scanning calorimetry also revealed increased thermal stability for some of the designs, indicating improved structural integrity.

Future Implications

The development of asymmetric Fc engineering represents a significant advancement in the field of bispecific antibodies. By carefully tuning the effector functions, researchers can create more precise and effective immunotherapies. These engineered antibodies hold great promise for treating a wide range of diseases, including cancer and autoimmune disorders. Further studies will be needed to evaluate their clinical potential and optimize their design for specific therapeutic applications.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.3390/antib6020007, Alternate LINK

Title: Asymmetric Fc Engineering For Bispecific Antibodies With Reduced Effector Function

Subject: Drug Discovery

Journal: Antibodies

Publisher: MDPI AG

Authors: Eric Escobar-Cabrera, Paula Lario, Jason Baardsnes, Joseph Schrag, Yves Durocher, Surjit Dixit

Published: 2017-05-16

Everything You Need To Know

What are bispecific antibodies, and why is it sometimes necessary to reduce or silence their effector functions?

Bispecific antibodies are designed to recognize two different targets simultaneously, allowing for novel functions that traditional antibodies cannot achieve. This dual-targeting approach is particularly useful in therapeutic strategies where reduced or silenced effector functions are needed. Uncontrolled effector activity, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), can lead to unintended side effects, especially when the antibody redirects immune cells or engages immunomodulatory targets.

What is asymmetric Fc engineering, and how does it improve the therapeutic profile of bispecific antibodies?

Asymmetric Fc engineering involves introducing different mutations on each arm of the Fc region of a bispecific antibody to fine-tune its activity. This approach offers greater control over effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and improves the antibody's overall therapeutic profile. By selectively reducing or silencing these effector functions, researchers can minimize unintended side effects and create more precise immunotherapies.

What are the key findings of the study on asymmetric Fc engineering regarding binding to FcyRs and C1q, as well as ADCC and CDC activity?

The key findings from the study on asymmetric Fc engineering include: (1) Reduced binding to Fc gamma receptors (FcyRs) and C1q, which are crucial for initiating immune responses. (2) A consistent reduction in antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity. (3) Increased thermal stability for some designs, indicating improved structural integrity. (4) Improved purification strategy using ion exchange chromatography, which allows for the efficient separation of heterodimeric antibodies from homodimeric impurities due to differences in their isoelectric point (pI).

How does asymmetric Fc engineering aid in the purification of bispecific antibodies, and why is this important?

Asymmetric Fc engineering in bispecific antibodies allows for the creation of heterodimeric molecules with distinct isoelectric points (pI), which facilitates their separation from homodimeric impurities using ion exchange chromatography. This is crucial for producing high-quality bispecific antibodies suitable for therapeutic use. The introduction of charged mutations in the lower hinge and CH2 domain of the Fc region creates these differences, enabling efficient purification and ensuring that the final product is highly pure and effective.

What are the future implications of asymmetric Fc engineering in the development of immunotherapies for diseases like cancer and autoimmune disorders?

The development of asymmetric Fc engineering represents a significant advancement in creating precise and effective immunotherapies. By carefully tuning the effector functions of bispecific antibodies, researchers can minimize unintended side effects and enhance their therapeutic potential for treating various diseases, including cancer and autoimmune disorders. Future studies will focus on evaluating their clinical potential and optimizing their design for specific therapeutic applications. The ability to reduce or silence effector functions like antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) is particularly important when redirecting immune cells or engaging immunomodulatory targets to avoid uncontrolled immune responses.