Eradication of human hepatic and pulmonary melanoma metastases in SCID mice by antibody-interleukin 2 fusion proteins.

Abstract

(8-10).An alternative means of cytokine delivery is to target them to tumor sites with mAbs directed against tumor associated antigens (11, 12). Thereby, effective local cytokine concentrations can be achieved at the tumor site without resorting to patient-specific therapy. A number of groups have reported the construction of such fusion proteins combining the antigen-binding capacity of antibodies or their fragments with the cytokine activity of IL-2 using different strategies for plasmid construction and protein expression (11)(12)(13) Mouse-human chimeric antibodies directed against the EGF receptor (ch225) or GD2 (chl4.18) were constructed by joining the cDNA for the variable region of the murine antibodies with the constant regions of the yl heavy chain and the K light chain as described (19). The antibody-IL-2 fusion

Trifunctional Bispecific Antibodies Induce Tumor-Specific T Cells and Elicit a Vaccination Effect

“…The latter is directed against GD2, a ganglioside that is expressed in human small cell lung cancer, glioma or melanoma and whose potential as target structure for tumor immunotherapy has been shown in vitro and in mouse tumor models (34)(35)(36). In particular, Ig-IL-2 fusion proteins (21,(37)(38)(39) and bsAbs (18) turned out to be effective reagents for initiating immune responses against tumor cells expressing this ganglioside. Thus, B78-D14 and the surrogate antibody Surek provide an appropriate animal model for establishing bsAb-mediated therapy of various types of human cancer.…”

Melanoma immunotherapy by targeted IL-2 depends on CD4+ T-cell help mediated by CD40/CD40L interaction

“…This can be accomplished by directing IL-2 into the tumor microenvironment with tumor-specific Ab-cytokine fusion proteins, called immunocytokines; this technique has been demonstrated in several xenograft and syngeneic preclinical animal models for colorectal carcinoma (29)(30)(31), prostate cancer (32), neuroblastoma (24,33), and melanoma (4)(5)(6)23). In two such model systems-murine colorectal carcinoma and melanoma-eradication of established metastases was mediated by CD8 + effector T cells.…”

“…The mouse-human chimeric Ab ch225-IL-2 control immunocytokine directed against the human EGF receptor has been described previously (23). The humanized anti-disialoganglioside GD 2 antibody hu14.18, and its fusion protein with hIL-2 were generated and provided by Lexigen Pharmaceuticals Corp. (Lexington, Massachusetts, USA).…”

Modified cytokeratins expressed on the surface of carcinoma cells undergo endocytosis upon binding of human monoclonal antibody and its recombinant Fab fragment

“…Consequently, we have now produced the recombinant Fab fragment of COU-1 by using the phage display technology, which allows molecular cloning of human antibodies, including those already immortalized by the hybridoma technique (8). A significant advantage is that cloning the antibody variable genes into a vector allows affinity maturation of the antibody (9, 10), grafting of different Fc regions onto it (11), as well as genetic engineering of immunotoxins (12) and immunomodifiers (13). In addition, the manufacturing cost may be less for recombinant human antibodies than for human hybridoma antibodies.…”