Anti-self antibodies selected from a human IgD heavy chain repertoire: a novel approach to generate therapeutic human antibodies against tumor-associated differentiation antigens.
Human antibodies were isolated by phage display from a naturally expressed human antibody repertoire. Antibody selection was carried out against the epithelial cell adhesion molecule (EpCAM) or 17-1A antigen, that in a clinical trial had been successfully used as a target for antibody therapy of minimal residual colorectal cancer. VH chains were selected from the human IgD repertoire expressed on naive B2 and autoreactive B1 lymphocytes. By guiding the selection through a murine template antibody, two EpCAM-specific human antibodies, HD69 and HD70, were obtained that closely resembled the murine therapeutic 17-1A antibody in their binding properties when expressed as complete huIgG1 molecules in CHO cells. However, both human antibodies recruited human cytotoxic effector cells far more efficiently than the murine 17-1A antibody used for clinical trials. Therefore, and in view of the long in vivo half-life of human IgG1 antibodies, HD69 and HD70 are regarded as highly promising third generation versions of the murine therapeutic antibody. Because of their origin from an evolutionary conserved germline VH repertoire, they are expected to exhibit minimal immunogenicity in patients.
Raum
T
T
Institut für Immunologie, Goethestrasse 31, 80336 Munich, Germany.
Gruber
R
R
Riethmüller
G
G
Kufer
P
P
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D016466:CHO Cells; D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000071858:Epithelial Cell Adhesion Molecule; D018604:Epitope Mapping; D005434:Flow Cytometry; D006801:Humans; D007072:Immunoglobulin D / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance; D014162:Transfection
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D019151:Peptide Library; D010455:Peptides