Fc engineering refers to the modification of the Fc region of antibodies to enhance their therapeutic properties, such as increasing their binding affinity to Fcγ receptors on immune cells, improving effector functions like antibody-dependent cellular cytotoxicity (ADCC), and extending their half-life in circulation.
Fig.1 Techniques to discover variants.1,2
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Fc Glycosylation: Glycosylation refers to the addition of sugar molecules to the Fc region of antibodies. Engineering the glycan composition can modulate antibody effector functions.
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Fc Engineering by Mutagenesis: Rational mutagenesis of the Fc region can improve antibody effector functions. Point mutations in the Fc domain, such as L234A/L235A (known as "LALA" mutations), can abrogate binding to Fcγ receptors, thereby reducing Fc-mediated effector functions like ADCC and complement-dependent cytotoxicity (CDC). Conversely, mutations like M252Y/S254T/T256E (known as "YTE" mutations) can increase FcγR binding affinity and serum half-life.
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Fc Fusion Proteins: Fc fusion proteins consist of an antibody Fc region fused to a therapeutic protein or peptide. This format combines the effector functions of antibodies with the therapeutic properties of the fused moiety.
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Bispecific Antibodies with Engineered Fc: Fc engineering in Bispecific antibodies (bsAbs) can modulate effector functions and pharmacokinetics. For instance, bsAbs with asymmetric Fc regions can selectively engage immune cells or block inhibitory pathways while sparing target cells from ADCC or CDC.
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Fc Silent Antibodies: In certain therapeutic contexts, reducing Fc-mediated effector functions may be desirable to minimize off-target effects or immunogenicity. Fc-silent antibodies, generated through Fc region modifications or masking techniques, retain antigen-binding specificity while attenuating Fcγ receptor interactions.
These Fc engineering technologies offer versatile strategies to optimize the therapeutic properties of antibodies and antibody-based therapeutics, facilitating the development of more efficacious and safer treatments for various diseases, including cancer, autoimmune disorders, and infectious diseases.
Creative Biolabs has a long history of research and development of the antibody ADCC effect, and offers a variety of Fc modification services to our customers in our Therapeutic Fc Engineering Technology unit, which you can find for more information.
Here, we share with you some of the latest research on Fc engineering retrofit technology to deepen your understanding of the field.
CH2 Domain Mutations Technology
Mutant Fc domains interact with key sites of Fcγ receptors and C1q, which can reduce or remove their binding capacity. Specific mutagenesis techniques allow for the determination of the region in which C1q binds to the antibody, including the hinge region and the CH2 domain above the Fc domain. CH2 domain mutation technology selectively regulates the interaction of antibodies with FcgR and C1q expressed on the surface of immune cells by mutating the CH2 domain in the Fc region of the antibody, thereby enhancing efficacy.
LALA Mutations Technology
A specific combination of amino acid mutations in the Fc region can alter the binding affinity of the antibody to FcγR, thereby altering the strength of the antibody's effector function. The most common LALA mutations (L234A/L235A) result in altered antibody affinity for FcγR (elimination of binding to low-affinity FcγR and decreasing binding to FcγRI), resulting in significantly reduced ADCC and CDC activity.
References
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Liu, Rena.; et al. "Fc-engineering for modulated effector functions-improving antibodies for cancer treatment." Antibodies. (2020) 9,4 64.
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