Interferon-? conjugation to human osteogenic sarcoma monoclonal antibody 791T/36

Abstract

Human lymphoblastoid interferon-alpha (IFN-alpha) has been coupled using N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) to a murine monoclonal antibody (791T/36) which reacts with antigens expressed on human osteogenic sarcomas. The purified conjugates retain antibody activity as defined by their capacity to compete with binding of fluorescein isothiocyanate-labelled 791T/36 antibody to 791T cells. IFN-alpha-791T/36 antibody conjugates synthesized with 125I-trace-labelled IFN-alpha and 131I-trace-labelled antibody also bound to 791T cells, but not to bladder carcinoma T24 cells. The conjugates also retain the capacity of free IFN to activate natural killer cells in human peripheral blood lymphocytes and show specific localization in human osteogenic sarcoma xenografts developing in immunodeprived mice. These findings establish that conjugates containing IFN linked to a monoclonal antibody reacting with osteogenic sarcoma-associated antigens have potential for targeted immunotherapy and in related investigations with antibody has been shown by gamma camera imaging of patients following infusion of 131I-labelled antibody to localize in primary osteogenic sarcomas.

CD20-targeted tetrameric interferon-α, a novel and potent immunocytokine for the therapy of B-cell lymphomas

“…44 Other groups have produced mAb-IFN-␣ made by chemical conjugation that revealed some of the potential clinical benefits of such constructs. 45,46 A recombinant mAb-IFN-␣ comprising murine IFN-␣ and an anti-HER2/neu mAb exhibited potent inhibition of a transgenic (HER2/neu) murine B-cell lymphoma in immunocompetent mice and was also capable of inducing a protective adaptive immune response with immunologic memory. 47 Based on an extensive literature, it is reasonable to expect that therapy with 20-2b will stimulate localized recruitment and activation of several immune cells, including NK, T4, T8, and dendritic cells, resulting in enhanced cytotoxicity and ADCC, and may potentially induce tumor-directed immunologic memory.…”

Cryoimmunologic Antitumor Effects Enhanced by Dendritic Cells in Osteosarcoma

“…In the 1970s, immunotherapy for osteosarcoma was reported by Southam et al [42], Neff and Enneking [34], and Campbell et al [5]. In the 1980s, new methods such as the use of interferons and Bacille de Calmette et Guérin were reported [22,24,36]. Another approach used antiidiotypic antibodies using T cells and liposome encapsulation [18,51,52].…”

“…This type of immunotherapy reportedly is effective for breast and prostate cancers [6,8,39]. Many groups have reported successful immunotherapy for osteosarcoma [5,15,18,20,22,24,25,33,34,36,42,51,52]. However, the ability to control metastatic lesions and local recurrence does not appear to be superior to other adjuvant treatments [2,7,13,23,29].…”

Localization of anti-osteogenic sarcoma monoclonal antibody 791T/36 in a primary human osteogenic sarcoma and its subsequent xenograft in immunodeprived mice

“…In addition to localization studies, 791T/36 antibody has been conjugated to the anti-tumour agents vindesine [25], methotrexate [10] and daunomycin [9], to yield products preferentially toxic for cells expressing the 791T/36-defined antigen, and also to interferon [19], where products retain the ability to activate NK cells [7]. These products all retain the ability to localize in osteogenic sarcoma xenografts and, at least with vindesine [25] and methotrexate (unpublished findings), can retard growth of xenografts.…”