To increase the druggability of monoclonal antibodies, many efforts have been made in optimizing the physicochemical properties and functions mediated by Fc fragment. As an expert in this field, Creative Biolabs offers Fc engineering of therapeutic antibody candidates using various technologies, such as amino acid substitution and exchanging larger amino acid stretches between different antibody isotypes. To better serve our clients, we can offer solutions tailored to meet your exact expectations.
Extensive laboratory and clinical evidence have demonstrated that antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) play a crucial role in the clearance of cancer cells by therapeutic antibodies. The pharmaceutical industry has invested heavily in the Fc engineering of antibodies to achieve higher affinity or binding selectivity for FcγR and, thus, conferring them enhanced killing of target cells by ADCC, CDC, and ADCP.
At present, most of the antibody therapeutics are of the IgG isotype (or predominantly IgG1). IgG1 is the most abundant antibody isotype in human serum. However, these IgG antibodies do not recognize the FcαRI receptor, which is constitutively expressed on many cells of the myeloid lineage, such as macrophages, neutrophils, and eosinophils. Namely, IgA isotype can elicit powerful cytotoxic action via FcαRI receptor binding but IgA antibodies have not been amenable to therapeutic development. The challenges associated with IgA expression and purification, and its inability to capitalize on the cytotoxic mechanisms have limited the use of this antibody isotype as a therapeutic. Thus, scientists have been working on combining the advantages of these two subtypes of antibodies to develop ‘new’ forms of antibodies.
Scientists have reported the engineering of an IgGA ‘cross-isotype’ antibody which combines selected effector functions of both IgG and IgA. Not only do engineered IgGA antibodies bind to human FcαRI with an affinity similar to that of IgA antibodies, but they also display binding to human FcγRI, FcγRIIa/b, and C1q with an affinity similar to that of IgG1 antibodies. Besides, IgGA exhibits a 3-fold lower dissociation constant with C1q as compared to IgG1, which translates to improved CDC activity.
Fig.1 Structural modifications of IgG antibodies.1
The example of cross-isotype antibodies demonstrated here with the engineering of IgGA offers a possibility for the generation of other types of cross-isotype antibodies that combine effector functions normally displayed by different isotypes, for example, IgG and IgE. Creative Biolabs is a well-recognized leader in the field of custom antibody engineering. We are dedicated to the development of cross-isotype antibodies with increased therapeutic potency. Please feel free to contact us for more information if you are interested in our protein engineering services.
Reference
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