Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1998-04-27
2000-10-31
Ungar, Susan
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
5303881, 53038815, 5303882, 530350, C07K 1600
Patent
active
061404705
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION
This invention relates to the preparation of human monoclonal anti-tumor scFv and V.sub.H antibodies derived from the antibody repertoires of cancer patients.
Among the various strategies for the treatment and prevention of cancer, immunotherapy has long occupied a central position. Although the clinical results have not lived up to early expectations, the remarkable recent advances in our understanding of the immune system and in our ability to manipulate it has refocused interest in cancer immunology. Antibodies and T-cells are extremely selective agents for targeting specific cell types. Human monoclonal antibodies provide the further advantage of weak immunogenicity in humans.
BACKGROUND OF THE INVENTION
A major focus of cancer immunology is on the isolation of antibodies that react selectively with human tumor cells, since the antibodies could have important applications for targeting diagnostic and therapeutic agents to tumors and for identifying tumorigenic antigens. The established approach has been to generate large panels of monoclonal antibodies from mice immunized with human tumor cells, and to screen the antibodies for reactivity against the tumor. Despite the enormous effort expended on this approach, few antibodies that react preferentially with human tumors, and none that react specifically with one type of tumor, have been reported.
These results are disappointing but not necessarily conclusive, because the antibodies were generated in an xenogeneic system. Human antigens are generally recognized as foreign by the murine system, and since the tumor antigens are predominately nonspecific, the murine response to human tumors will be correspondingly nonspecific.
Another approach involves generating human monoclonal antibodies from cancer patients by cloning lymphocytes transformed with Epstein-Barr virus or fused with myeloma or B-lymphoblastoid cells. However, the number of clones that can be produced with these procedures is severely limited by technical obstacles, and the antibodies isolated from the clones have shown specificities similar to those obtained with murine monoclonal antibodies.
Further attempts to isolate more specific antibodies will require improved methods of generating and selecting antibodies against human tumors. Two recent developments may be useful in this regard. One involves immunizing cancer patients with autologous tumor cells which have been genetically modified to boost the immunogenicity of the cells (Dranoff, G. & Mulligan, R. C. (1995) Adv. Immunol. 58, 417-454). Although there is an extensive normal human repertoire of anti-self antibodies (Griffiths A. D., et al., (1993) EMBO J 12, 725-734), indicating that the human immune system can respond toself antigens, the humoral response of the immunized cancer patients might be directed preferentially against any non-self antigens expressed by the autologous or allogeneic tumor cells. Numerous such immunization trials are in progress with melanoma, renal and colon carcinoma, neuroblastoma and breast cancer patients, and others are planned.
The other new development is the introduction of methods for synthesizing virtually the entire repertoire of any person's antibody genes, and for expressing the encoded Fab or scFv antibody fragments on the surface of a fusion-phage vector (see, for example, Marks, J., et al., (1991) J. Mol. Biol. 222, 581-597). The resulting fusion-phage antibody library can be panned to select and clone rare antibodies on the basis of their binding specificities.
SUMMARY OF THE INVENTION
One object of the invention is to provide a new procedure for isolating human monoclonal anti-tumor scFv and V.sub.H antibodies from cancer patients. The use of V.sub.H as well as scFv antibodies is an important innovative modification of the procedure.
It is a further and more specific object of the invention to provide human monoclonal anti-tumor antibodies that are specific against one or more types of tumors, or a specific tumor lineage, and human monoclonal anti-end
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Cai Xiaohang
Garen Alan
Krinsky Mary M.
Ungar Susan
Yale University
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