Augmentation of tumor antigen expression by recombinant human interferons: enhanced targeting of monoclonal antibodies to carcinomas.
The use of Mabs for the detection and treatment of human carcinoma lesions can still be regarded in its infancy. As with other new approaches to cancer therapy, several conceptual as well as real problems exist when designing clinical protocols for Mab-directed immunotherapy. From the Mab standpoint, studies using the intact IgG have shown that, in a majority of patients injected with IgG, human anti-mouse IgG antibodies develop that hamper the effectiveness of subsequent antibody administration. It is believed that the human anti-mouse antibody response is directed against the Fc region of the IgG molecule. The elimination of this region through fractionation of the Mab to obtain the minimum binding site could result in a less immunogenic molecule. Another approach aimed at reducing the immunogenicity of the Mab would be to clone the genes encoding for individual Mabs, reduce them via restriction endonuclease techniques, and insert human immunoglobulin constant regions. The resulting chimeric antibodies are believed to reduce the development of human anti-mouse antibodies. Effective Mab therapy of human tumor lesions may also be achieved through the recruitment of a portion of the host's immunologic defense system. An example is the use of anti-idiotype Mabs that use as immunogen a Mab to a tumor antigen. The anti-idiotype antibodies are selected for binding to the antigen binding, or idiotype, region of the first Mab. The binding sites of the new anti-idiotype Mabs should reflect the 'internal image' of the original antigen. The anti-idiotype antibodies may be used to immunize patients (i.e., vaccines) in an attempt to mount an active immune response against the antigen-positive tumor cells. Recent studies have shown a synergism between interferon-alpha and an anti-idiotype Mab for the in-vivo antitumor activity in a murine B-cell lymphoma experimental model. Whether an interferon-mediated increase in the tumor antigen or the Fc receptor was part of the synergism was not investigated. Mabs alone have also been shown to elicit cytotoxic activity in vitro and tumoricidal activity in vivo. Antibodies of the IgG2a isotype can direct macrophage-mediated cytotoxicity. These studies revealed the importance of the number of antibody sites per cell as well as the number of cells that bind the IgG2a Mab, thus suggesting a 'threshold' requirement for the demonstration of effective tumor cell lysis in vitro and in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
Greiner
J W
JW
Guadagni
F
F
Hand
P H
PH
Pestka
S
S
Noguchi
P
P
Fisher
P B
PB
Schlom
J
J
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000032:analysis*; D002272:Carcinoembryonic Antigen / Q000032:analysis; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D009369:Neoplasms / Q000000981:diagnostic imaging*; D011877:Radionuclide Imaging; D011994:Recombinant Proteins
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D006023:Glycoproteins; D007370:Interferon Type I; D011994:Recombinant Proteins; C047052:tumor-associated antigen 72; D007371:Interferon-gamma