Humanization

Fig.1 Humanized antibodies and their non-human CDR region.

Immunogenic responses to antibody therapeutics can impact both safety and pharmacokinetic properties which can impact the utility and efficacy of the drugs. The goal of antibody humanization is to convert a nonhuman monoclonal antibody to be as humanlike as possible with respect to immunogenicity, but without losing the antigen specificity and binding affinity of the original antibody. Humanization is now a well-established technique by grafting complementary-determining region (CDR) where antibodies bind antigens via flexible loops. Humanization reduces the immunogenicity of monoclonal antibodies (mAbs) from xenogeneic sources and improves their activation of the human immune system. In fact, there are many humanized mAbs in clinical trials and a few have been given approval to be used as drugs. Humanized antibodies account for 34.7% of all mAbs in clinical use.

Methods of Humanization

A common method for the humanization of non-human antibodies is CDR grafting in which the CDRs of non-human antibodies are grafted onto the human frameworks. However, simple grafting of non-human CDRs into human frameworks does not always reconstitute the binding affinity and specificity of the original mAb. Unlike the conventional CDR-grafting approach, humanization by CDR homology were found to retain a significantly higher affinity. To reduce the immunogenicity of CDR-grafted humanized antibodies, the grafted regions may be further restricted to the specificity-determining residues (SDRs) which are the most important residues involved in antibody-antigen interaction within the CDRs. Nevertheless, CDR-grafting seems likely most popular. Moreover, humanization via variable domain resurfacing is based on identification of the accessible and protruding residues in the non-human antibody that need to be changed to human sequences without influencing the conformation of the CDR loops to produce humanized antibodies with reduced immunogenicity. Different from CDR grafting, however, resurfacing retains the non-exposed residues of the non-human antibody.

Fig.2 Chimeric antibodies and humanized antibodies. (Fan, 2017)

Humanized vs Chimeric Antibody

Recombinant antibody technology is paving anew way for the development of therapeutic and diagnostic agents. Chimeric and humanized antibodies are two types of non-human antibodies. If the constant region and part of the variable region are replaced, they are called humanized. If only the constant region is modified they are called chimeric. When comparing them, humanized antibodies carry a lower risk of immunogenicity than chimeric antibodies.

Application of Humanized Antibodies

Antibody humanization is an increasingly popular technique for the development of therapeutic antibodies. These antibodies are now recurrently applied for the treatment of cancer, autoimmune and genetic diseases, asthma, cardiovascular and hematologic diseases, and macular degeneration, among others. The use of humanized antibodies has helped greatly to improve clinical tolerance of mAb therapeutics.

Creative Biolabs has developed an integrated antibody humanization and affinity maturation platform based on the advanced phage/yeast display, recombinant DNA technologies and extensive antibody modeling and engineering expertise. Our antibody humanization service features to its low back mutation (usually lower than six amino acids) that can reduce the immunogenicity of antibody. Please feel free to contact us to start your projects.

References

1. Fan, G.; Li, J. Engineering antibodies for the treatment of infectious diseases. Recombinant Antibodies for Infectious Diseases. 2017: 207-220.
2. Kipriyanov, S.M.; Le Gall, F. Generation and production of engineered antibodies. Molecular biotechnology. 2004, 26 (1): 39-60.

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