SDR grafting—a new approach to antibody humanization

Kashmiri, S. V. S.; Pascalis, Roberto De; Gonzales, Noreen R.; Schlom, Jeffrey

doi:10.1016/j.ymeth.2005.01.003

Cited by 80 publications

(41 citation statements)

References 32 publications

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“…This method leaves only the CDRs with xenogeneic residues. [7][8][9][10] Despite this, the human anti-human antibody (HAHA) responses can still be problematic when treating with humanized antibodies. 2,[10][11][12][13][14] There is still murine content in the CDR and the HAHA response is usually associated with epitopes that at least partially contain CDR residues.…”

Section: Introductionmentioning

confidence: 99%

“…The former approach includes use of only the murine residues from the specificitydetermining residues (SDRs), i.e., the residues that are essential for the binding of the antibody to the ligand, along with multiple human germline sequences as templates. 9,17,18 "Superhumanization" uses a CDR homology based approach to antibody humanization and effectively selects a germline with CDRs that most closely match the murine CDRs. 19,20 An additional method includes screening for germline segments while only grafting the CDR3 of the heavy and light chain.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Apgar

Mader

Agostinelli

et al. 2016

mAbs

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Antibodies are an important class of biotherapeutics that offer specificity to their antigen, long half-life, effector function interaction and good manufacturability. The immunogenicity of non-human-derived antibodies, which can be a major limitation to development, has been partially overcome by humanization through complementarity-determining region (CDR) grafting onto human acceptor frameworks. The retention of foreign content in the CDR regions, however, is still a potential immunogenic liability. Here, we describe the humanization of an anti-myostatin antibody utilizing a 2-step process of traditional CDR-grafting onto a human acceptor framework, followed by a structure-guided approach to further reduce the murine content of CDR-grafted antibodies. To accomplish this, we solved the co-crystal structures of myostatin with the chimeric (Protein Databank (PDB) id 5F3B) and CDR-grafted antimyostatin antibody (PDB id 5F3H), allowing us to computationally predict the structurally important CDR residues as well as those making significant contacts with the antigen. Structure-based rational design enabled further germlining of the CDR-grafted antibody, reducing the murine content of the antibody without affecting antigen binding. The overall "humanness" was increased for both the light and heavy chain variable regions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Apgar

Mader

Agostinelli

et al. 2016

mAbs

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“…The next approach was, therefore, the use of specificity-determining residue (SDR) grafting, in which only the SDRs (not whole CDRs) are grafted onto the germline antibodies. These SDR-grafted humanized antibodies indeed showed lower immunogenicity than CDR-grafted humanized antibodies [379][380][381][382].…”

Section: Humanized Antibodiesmentioning

confidence: 90%

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Klein

Templeton

Schwenk

2014

Pure and Applied Chemistry

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This report discusses the history and mechanisms of vaccination of humans as well as the engineering of therapeutic antibodies. Deeper understanding of the molecular interactions involved in both acquired and innate immunity is allowing sophistication in design of modified and even synthetic vaccines. Recombinant DNA technologies are facilitating development of DNA-based vaccines, for example, with the recognition that unmethylated CpG sequences in plasmid DNA will target Toll-like receptors on antigen-presenting cells. Formulations of DNA vaccines with increased immunogenicity include engineering into plasmids with "genetic adjuvant" capability, incorporation into polymeric or magnetic nanoparticles, and formulation with cationic polymers and other polymeric and non-polymeric coatings. Newer methods of delivery, such as particle bombardment, DNA tattooing, electroporation, and magnetic delivery, are also improving the effectiveness of DNA vaccines. RNA-based vaccines and reverse vaccinology based on gene sequencing and bioinformatic approaches are also considered. Structural vaccinology is an approach in which the detailed molecular structure of viral epitopes is used to design synthetic antigenic peptides. Virus-like particles are being designed for vaccine deliveries that are based on structures of viral capsid proteins and other synthetic lipopeptide building blocks. A new generation of adjuvants is being developed to further enhance immunogenicity, based on squalene and other oil-water emulsions, saponins, muramyl dipeptide, immunostimulatory oligonucleotides, Toll-like receptor ligands, and lymphotoxins. Finally, current trends in engineering of therapeutic antibodies including improvements of antigen-binding properties, pharmacokinetic and pharmaceutical properties, and reduction of immunogenicity are discussed. Taken together, understanding the chemistry of vaccine design, delivery and immunostimulation, and knowledge of the techniques of antibody design are allowing targeted development for the treatment of chronic disorders characterized by continuing activation of the immune system, such as autoimmune disorders, cancer, or allergies that have long been refractory to conventional approaches.

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“…Les avancées scientifiques dans ce domaine ne se sont pas faites sans obstacles. En effet, les scientifiques ont été confrontés d'une part à des problèmes d'immunogénicité dus à la fois à la nature et à l'origine des molécules [3], d'autre part aux connaissances limitées sur l'impact de la qualité du produit fini, par exemple l'effet de l'agrégation [4]. Les avancées des techniques de génie génétique ( utilisation d'anticorps murins, puis partiellement, voire totalement humanisés (➜), ainsi qu'agonistes et antagonistes, etc.)…”

Section: Anticorps Thérapeutiquesunclassified