title: Human antibodies for immunotherapy development generated via a human B cell hybridoma technology.
abstract: Current strategies for the production of therapeutic mAbs include the use of mammalian cell systems to recombinantly produce Abs derived from mice bearing human Ig transgenes, humanization of rodent Abs, or phage libraries. Generation of hybridomas secreting human mAbs has been previously reported; however, this approach has not been fully exploited for immunotherapy development. We previously reported the use of transient regulation of cellular DNA mismatch repair processes to enhance traits (e.g., affinity and titers) of mAb-producing cell lines, including hybridomas. We reasoned that this process, named morphogenics, could be used to improve suboptimal hybridoma cells generated by means of ex vivo immunization and immortalization of antigen-specific human B cells for therapeutic Ab development. Here we present a platform process that combines hybridoma and morphogenics technologies for the generation of fully human mAbs specific for disease-associated human antigens. We were able to generate hybridoma lines secreting mAbs with high binding specificity and biological activity. One mAb with strong neutralizing activity against human granulocyte-macrophage colony-stimulating factor was identified that is now considered for preclinical development for autoimmune disease indications. Moreover, these hybridoma cells have proven suitable for genetic optimization using the morphogenics process and have shown potential for large-scale manufacturing.
authors.affiliation: Morphotek, Inc., 210 Welsh Pool Road, Exton, PA 19341, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Sai
authors.forename: Marc
authors.initials: M
authors.lastname: Berger
authors.forename: Qimin
authors.initials: Q
authors.lastname: Chao
authors.forename: Diane
authors.initials: D
authors.lastname: Davidson
authors.forename: Gaurav
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Brian
authors.initials: B
authors.lastname: Drozdowski
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Ebel
authors.forename: Stephen
authors.initials: S
authors.lastname: Harley
authors.forename: Marianne
authors.initials: M
authors.lastname: Henry
authors.forename: Sara
authors.initials: S
authors.lastname: Jacob
authors.forename: Brad
authors.initials: B
authors.lastname: Kline
authors.forename: Ella
authors.initials: E
authors.lastname: Lazo
authors.forename: Frank
authors.initials: F
authors.lastname: Rotella
authors.forename: Eric
authors.initials: E
authors.lastname: Routhier
authors.forename: Kathryn
authors.initials: K
authors.lastname: Rudolph
authors.forename: Jeaneen
authors.initials: J
authors.lastname: Sage
authors.forename: Paul
authors.initials: P
authors.lastname: Simon
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Mani
authors.initials: M
authors.lastname: Kavuru
authors.forename: Tracey
authors.initials: T
authors.lastname: Bonfield
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Thomassen
authors.forename: Philip M
authors.initials: PM
authors.lastname: Sass
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Nicolaides
authors.forename: Luigi
authors.initials: L
authors.lastname: Grasso
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000627:therapeutic use*; D000941:Antigens / Q000235:genetics; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy; D001402:B-Lymphocytes / Q000276:immunology*; D020137:Base Pair Mismatch; D002478:Cells, Cultured; D004260:DNA Repair; D000939:Epitopes / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D006825:Hybridomas / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007167:Immunotherapy / Q000379:methods*; D066298:In Vitro Techniques; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D000939:Epitopes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor