دورية أكاديمية
أعرض في EDS

Augmented Binary Substitution: Single-pass CDR germ-lining and stabilization of therapeutic antibodies.

التفاصيل البيبلوغرافية
العنوان: Augmented Binary Substitution: Single-pass CDR germ-lining and stabilization of therapeutic antibodies.
المؤلفون: Townsend S; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Fennell BJ; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Apgar JR; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Cambridge, MA 02139;, Lambert M; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, McDonnell B; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Grant J; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Wade J; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Franklin E; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Foy N; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Ní Shúilleabháin D; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Fields C; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Darmanin-Sheehan A; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, King A; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Cambridge, MA 02139;, Paulsen JE; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Cambridge, MA 02139;, Hickling TP; Pharmacokinetics, Dynamics and Metabolism, Pfizer Biotherapeutics R&D, Andover, MA 01810., Tchistiakova L; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Cambridge, MA 02139;, Cunningham O; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland;, Finlay WJ; Global Biotherapeutics Technologies, Pfizer Biotherapeutics R&D, Dublin D22, Ireland; william.finlay@pfizer.com.
المصدر: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2015 Dec 15; Vol. 112 (50), pp. 15354-9. Date of Electronic Publication: 2015 Nov 30.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : National Academy of Sciences
مواضيع طبية MeSH: Antibodies, Monoclonal/*immunology , Antibodies, Monoclonal/*therapeutic use , Complementarity Determining Regions/*immunology , Germ Cells/*immunology, Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/chemistry ; Antibody Specificity/immunology ; Clone Cells ; Complementarity Determining Regions/chemistry ; Computer Simulation ; Enzyme-Linked Immunosorbent Assay ; Epitopes, T-Lymphocyte/immunology ; Humans ; Immunoglobulin G/chemistry ; Immunoglobulin G/immunology ; Immunoglobulin Heavy Chains/chemistry ; Immunoglobulin Heavy Chains/immunology ; Immunoglobulin Light Chains/chemistry ; Immunoglobulin Light Chains/immunology ; Immunoglobulin Variable Region/chemistry ; Immunoglobulin Variable Region/immunology ; Models, Molecular ; Molecular Sequence Data ; Mutation/genetics ; Peptide Library ; Protein Stability ; Protein Structure, Tertiary ; Rats ; Sequence Alignment ; Sequence Analysis, Protein ; tau Proteins/chemistry ; tau Proteins/immunology
مستخلص: Although humanized antibodies have been highly successful in the clinic, all current humanization techniques have potential limitations, such as: reliance on rodent hosts, immunogenicity due to high non-germ-line amino acid content, v-domain destabilization, expression and formulation issues. This study presents a technology that generates stable, soluble, ultrahumanized antibodies via single-step complementarity-determining region (CDR) germ-lining. For three antibodies from three separate key immune host species, binary substitution CDR cassettes were inserted into preferred human frameworks to form libraries in which only the parental or human germ-line destination residue was encoded at each position. The CDR-H3 in each case was also augmented with 1 ± 1 random substitution per clone. Each library was then screened for clones with restored antigen binding capacity. Lead ultrahumanized clones demonstrated high stability, with affinity and specificity equivalent to, or better than, the parental IgG. Critically, this was mainly achieved on germ-line frameworks by simultaneously subtracting up to 19 redundant non-germ-line residues in the CDRs. This process significantly lowered non-germ-line sequence content, minimized immunogenicity risk in the final molecules and provided a heat map for the essential non-germ-line CDR residue content of each antibody. The ABS technology therefore fully optimizes the clinical potential of antibodies from rodents and alternative immune hosts, rendering them indistinguishable from fully human in a simple, single-pass process.
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فهرسة مساهمة: Keywords: antibody; humanization; immunogenicity; paratope; plasticity
المشرفين على المادة: 0 (Antibodies, Monoclonal)
0 (Complementarity Determining Regions)
0 (Epitopes, T-Lymphocyte)
0 (Immunoglobulin G)
0 (Immunoglobulin Heavy Chains)
0 (Immunoglobulin Light Chains)
0 (Immunoglobulin Variable Region)
0 (Peptide Library)
0 (tau Proteins)
تواريخ الأحداث: Date Created: 20151202 Date Completed: 20160509 Latest Revision: 20181113
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC4687607
DOI: 10.1073/pnas.1510944112
PMID: 26621728
قاعدة البيانات: MEDLINE
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.1510944112