Abstract
The remarkable progress in engineering and clinical development of therapeutic antibodies in the last 40 years, after the seminal work by Köhler and Milstein, has led to the approval by the United States Food and Drug Administration (FDA) of 21 antibodies for cancer immunotherapy. We review here these approved antibodies, with emphasis on the methods used for their discovery, engineering, and optimization for therapeutic settings. These methods include antibody engineering via chimerization and humanization of non-human antibodies, as well as selection and further optimization of fully human antibodies isolated from human antibody phage-displayed libraries and immunization of transgenic mice capable of generating human antibodies. These technology platforms have progressively led to the development of therapeutic antibodies with higher human content and, thus, less immunogenicity. We also discuss the genetic engineering approaches that have allowed isotype switching and Fc modifications to modulate effector functions and bioavailability (half-life), which together with the technologies for engineering the Fv fragment, have been pivotal in generating more efficacious and better tolerated therapeutic antibodies to treat cancer.
Highlights
The hybridoma technology developed in the mid-1970s by Köhler and Milstein [1] proved to be an efficient means to isolate single specificity antibodies and produce them in unlimited amounts
This review focuses on these antibodies, lessons learned from their engineering and clinical development, as well as challenges and prospects to generate more efficacious therapeutic antibodies
antibody–drug conjugates (ADCs) and bispecific modalities are not reviewed here due to the vast amount of information published in this field, compounded with space limitations, it should be highlighted that the methods for discovery and optimization of V regions and modifications of the fragment cyrstallizable (Fc) to tailor the effector functions to a given mechanisms of action (MOA), are common and can be applied to all antibody-based modalities
Summary
The remarkable progress in engineering and clinical development of therapeutic antibodies in the last 40 years, after the seminal work by Köhler and Milstein, has led to the approval by the United States Food and Drug Administration (FDA) of 21 antibodies for cancer immunotherapy We review here these approved antibodies, with emphasis on the methods used for their discovery, engineering, and optimization for therapeutic settings. These methods include antibody engineering via chimerization and humanization of non-human antibodies, as well as selection and further optimization of fully human antibodies isolated from human antibody phage-displayed libraries and immunization of transgenic mice capable of generating human antibodies These technology platforms have progressively led to the development of therapeutic antibodies with higher human content and, less immunogenicity.
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