Antibody-based immunological therapies

doi:10.1016/S0952-7915(97)80054-4

Current Opinion in Immunology

Volume 9, Issue 5, October 1997, Pages 717-722

https://doi.org/10.1016/S0952-7915(97)80054-4 Get rights and content

Abstract

Clinical research in the area of antibody-based tumor-targeted therapy has been driven for many years by the prospect of identifying cell surface antigens with sufficient restrictive tissue expression patterns to allow for the selective and specific accumulation of antibody in tumor tissue. Few, if any, such antibody—antigen systems have been identified which can effectively deliver a large fraction of an administered therapeutic agent to metastatic cancer. Despite this limitation, however, a greater understanding of the biological and physiological principles of tumor-targeted therapy has resulted in successful antibody-based therapy of lymphoma, colon cancer and breast cancer in recent clinical trials.

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Traditional strategies for the identification of cell-surface cancer targets often fall short of their objective. For example, whole-cell panning of antibody libraries to isolate a diverse panel of antibodies directed against targets on cancer cells often identifies all immunogenic and/or abundant cell-surface antigens, not simply tumor-specific or tumor-associated antigens. Here we describe the use of stringent negative selection in combination with positive panning to increase tumor specificity and clinical relevance of selected antibodies. Sera from cancer cell-immunized mice showed strong binding to immunizing cancer cell lines but also cross-reacted strongly with human blood cells. Antisera blood cell binding was considerably decreased after stringent subtraction with human red blood cells (RBCs) and white blood cells (WBCs), yet cancer cell specificity was retained. In order to select for a higher percentage of clinically relevant antibodies for potential therapeutic use, stringent negative selection by RBC subtraction was employed in whole-cell panning of a disease-specific phage displayed antibody library on the prostate cancer cell line, PC-3. Isolated antibodies were found to bind to target antigens implicated in tumorigenicity and cancer cell migration and/or invasion, and included CD26, CDCP1, and the integrin complexes α2/β1, α3/β1, α5/β1, and α6/β4. Compared with traditional cell panning, this method considerably increased the selectivity of antibodies to tumor-associated antigens.
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Antibodies targeting human epithelial carcinomas bearing Lewis Y (Le^y) carbohydrate antigens provide a striking illustration of convergent immune recognition. We report a 1.9 Å resolution crystal structure of the Fab of a humanized antibody (hu3S193) in complex with the Le^y tetrasaccharide, Fuc(α1→2)Gal(β1→4)[Fuc(α1→3)]GlcNAc. Comparisons of the hu3S193 and BR96 antibodies bound to Le^y tumor antigens revealed extremely similar mechanisms for recognition of the carbohydrate epitopes. Solvent plays a critical role in hu3S193 antibody binding to the Le^y carbohydrate epitope. Specificity for Le^y is maintained because a conserved pocket accepts an N-acetyl group of the core Gal(β1→4)GlcNAc disaccharide. Closely related blood-group determinants (Le^a and Le^b) cannot enter the specificity pocket, making the Le^y antibodies promising candidates for immunotherapy of epithelial cancer.
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View full text

Antibody-based immunological therapies

Abstract

Blood

Leukemia

Cancer Res

Blood

Lancet

Cancer Res

Cancer Res

Continuous cultures of fused cells secreting antibody of predefined specificity

Nature

Immunotherapy for cancer

Sci Am

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Lancet

Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma

J Clin Oncol

Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas

Lancet

Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoms

Clin Cancer Res

Treatment of non-Hodgkin's lymphoma with radiolabelled murine, chimeric, or humanised LL2, an anti-CD22 monoclonal antibody

Cancer Res

A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma

Blood

A phase IB trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity

Blood

Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia

J Clin Oncol

Radioimmunotherapy of interleukin-2Rα-expressing adult T-cell leukemia with yttrium-90-labeled anti-Tac

Blood

Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies

Proc Natl Acad Sci USA

Humoral anti-idiotypic and anti-anti-idiotypic immune response in cancer patients treated with monoclonal antibody 17-1A

Cancer Immunol Immunother

High-dose therapy using the iodine-131-labeled monoclonal antibody CC49 in patients with gastrointestinal cancers: a phase I trial

J Clin Oncol

Phase I/II study of 131Iodine-labeled monoclonal antibody A33 in patients with advanced colon cancer

J Clin Oncol

Phase I/II study of iodine-125-labeled monoclonal antibody A33 in patients with advanced colon cancer

J Clin Oncology

Phase II trial of ¹³¹I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas

Phase I/II study of ¹³¹Iodine-labeled monoclonal antibody A33 in patients with advanced colon cancer