Results of Early Trials Using Murine Monoclonal Antibodies as Anticancer Therapy

Dillman, Robert O.; Beauregard, J; Shawler, DL; Sobol, Robert E.; Royston, Ivor

doi:10.1016/b978-0-08-029815-3.50082-9

Cited by 6 publications

(2 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…T65 is expressed on normal T cells, T cell leukemias and lymphomas, chronic lymphocytic leukemia (CLL), and cutaneous T cell lymphoma (CTCL) cells [166][167][168][169][170].…”

Section: )mentioning

confidence: 99%

Genetically Engineered Monoclonal Antibodies for Direct Anti-Neoplastic Treatment and Cancer Cell Specific Delivery of Chemotherapeutic Agents

Bodey

Siegel²,

Kaiser³

2000

CPD

View full text Add to dashboard Cite

Classical therapeutic modalities such as surgery, radiation, and chemotherapy not only fail to cure the great majority of malignant tumors, but their employment often leads to severe and debilitating side effects. The severe cancer related morbidity is also in direct correlation with the use of x-radiation and chemotherapy, making them less than ideal forms of therapy. The development of hybridoma technology and the advances in monoclonal antibody (MoAB) production have revitalized the initial concept of Ehrlich concerning the existence of cancer cell-targeted, specific "magic bullets". Entirely new approaches to cancer therapy that are neoplastic cell-directed, and specifically lethal to malignant cells and less toxic to normal tissues are being observed and developed, adhering to the old prayer: "Destroy the diseased tissues, preserve the normal." Immunotherapy as a fourth modality of cancer therapy has already been developed and proven to be quite effective. Strategies for the employment of antibodies for anti-cancer immunotherapy include: 1) Immune reaction directed destruction of cancer cells; 2) Interference with the growth and differentiation of malignant cells; 3) Antigen epitope directed transport of anti-cancer agents to malignant cells; 4) Anti-idiotype vaccines; and 5) Development of engineered (humanized) mouse monoclonals for anti-cancer therapy. In addition, a variety of different agents (e.g. toxins, radionuclides, chemotherapeutic drugs) have been conjugated to mouse and human MoABs for selective delivery to cancer cells. Preclinical observations in athymic, nude mice using xenografted human cancers and mouse, anti-human MoABs were more than impressive and have lead to the development of clinical trials. Phase I studies established the safety of employing immunoconjugates in humans, but the in vivo therapeutic results were less impressive. The clinical use of mouse MoABs in humans is limited due to the development of a foreign anti-globulin immune response by the human host. Genetically engineered chimeric human-mouse MoABs have been developed by replacing the mouse Fc region with the human constant region. Moreover, the framework regions of variable domains of rodent immunoglobulins were also experimentally replaced by their human equivalents. These antibodies can also be designed to have specificities and effector functions determined by researchers, which may not appear in nature. The development of antibodies with two binding ends (bispecific antibodies) provided a great improvement in targeting cancer cells. The existing inadequacies of MoABs in immunotherapy may also be improved by increasing their efficiency with chemical coupling to various agents such as bacterial or plant toxins, radionuclides or cytotoxic drugs. The astonishing immunophenotypic (IP) heterogeneity of neoplastically transformed cells, the different cytotoxic activity associated with the moiety linked to given MoABs, and mostly the impressive genetic modulation capabilities of cancer cells still remain as yet unsolved dif...

show abstract

“…T65 is expressed on normal T cells, T cell leukemias and lymphomas, chronic lymphocytic leukemia (CLL), and cutaneous T cell lymphoma (CTCL) cells [166][167][168][169][170].…”

Section: )mentioning

confidence: 99%

Genetically Engineered Monoclonal Antibodies for Direct Anti-Neoplastic Treatment and Cancer Cell Specific Delivery of Chemotherapeutic Agents

Bodey

Siegel²,

Kaiser³

2000

CPD

View full text Add to dashboard Cite

show abstract

“…For B72.3, the highest substitution level that could be achieved without adversely affecting the ELISA titration curve was found to be approximately 3 chelators per antibody molecule, this substitution level being achieved at a charging stoichiometry of 5 mol of chelator per mol of immunoglobulin under the conditions .67 (0.03) 11. 23 (5.51) 19.82 (0.62) 12.1 (2.8) 18.37 (0.28) 8.9 (1.4) tumor (Ag +) 18.97 (0.09) 42.22 (15.14) 20.82 (0.05) 21.1 (4.6) 25.94 (1.01) 19.5 (2.3) tumor (Ag -)…”

mentioning

confidence: 99%

Synthesis of novel bifunctional chelators and their use in preparing monoclonal antibody conjugates for tumor targeting

Westerberg

Carney²,

Rogers³

et al. 1989

J. Med. Chem.

View full text Add to dashboard Cite

Bifunctional derivatives of the chelating agents ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid, in which a p-isothiocyanatobenzyl moiety is attached at the methylene carbon atom of one carboxymethyl arm, was synthesized by reductive alkylation of the relevant polyamine with (p-nitrophenyl)pyruvic acid followed by carboxymethylation, reduction of the nitro group, and reaction with thiophosgene. The resulting isothiocyanate derivatives reacted with monoclonal antibody B72.3 to give antibody-chelator conjugates containing 3 mol of chelator per mole of immunoglobulin, without significant loss of immunological activity. Such conjugates, labeled with the radioisotopic metal indium-111, selectively bound a human colorectal carcinoma implanted in nude mice when given intravenously. Uptake into normal tissues was comparable to or lower than that reported for analogous conjugates with known bifunctional chelators. It is concluded that substitution with a protein reactive group at this position in polyaminopolycarboxylate chelators does not alter the chelating properties of these molecules to a sufficient extent to adversely affect biodistribution and thus provides a general method for the synthesis of such chelators.

show abstract

Toxicity of monoclonal antibodies in the treatment of cancer

Dillman

1988

Seminars in Oncology Nursing

View full text Add to dashboard Cite

Results of Early Trials Using Murine Monoclonal Antibodies as Anticancer Therapy

Cited by 6 publications

References 9 publications

Genetically Engineered Monoclonal Antibodies for Direct Anti-Neoplastic Treatment and Cancer Cell Specific Delivery of Chemotherapeutic Agents

Genetically Engineered Monoclonal Antibodies for Direct Anti-Neoplastic Treatment and Cancer Cell Specific Delivery of Chemotherapeutic Agents

Synthesis of novel bifunctional chelators and their use in preparing monoclonal antibody conjugates for tumor targeting

Toxicity of monoclonal antibodies in the treatment of cancer

Contact Info

Product

Resources

About