Active specific immunotherapy in patients with melanoma. A clinical trial with mouse antiidiotypic monoclonal antibodies elicited with syngeneic anti-high-molecular-weight-melanoma-associated antigen monoclonal antibodies.

Abstract

IntroductionIn two clinical trials the mouse antiidiotypic monoclonal antibody (MAb) MF1 1-30, which bears the internal image of human high-molecular-weight-melanoma-associated antigen (HMW-MAA) was administered by subcutaneous route without adjuvants to patients with stage IV malignant melanoma on day 0, 7, and 28. The development of monoclonal antibodies to human tumorassociated antigens (TAA)' that meet the criteria to be used as targets for immunotherapy (for review, see 1-3) has rekindled interest in the application of immunotherapeutic approaches to malignant diseases. Among them, the use of antiidiotypic antibodies, i.e., antibodies to determinants expressed on the variable region of anti-TAA antibodies, is attracting much attention, since in animal model systems the immune response induced by this type of active specific immunotherapy is associated with an improvement of the course of the disease (4-6). The rationale underlying this approach is represented by the ability ofantiidiotypic antibodies that bear the mirror image of TAA to elicit and/or enhance anti-TAA immune responses; such responses may eventually result in the destruction of tumor cells.In order to test the usefulness of mouse antiidiotypic MAb elicited with syngeneic anti-TAA MAb to implement active specific immunotherapy, we have selected malignant melanoma as our model system for a number of reasons (7). First, a therapeutic approach based on manipulation of the patient's immune response has a potential for success in this disease because ofthe likely role of immunological factors in its pathogenesis and in its clinical course (8). Second, testing of a novel therapeutic approach finds justification in the lack of progress and limited success of available therapeutic modalities in malignant melanoma (9). Third, utilizing mouse MAb, we have identified a membrane-bound melanoma-associated antigen, referred to as HMW-MAA (high-molecular-weight-melanoma-associated antigen). This antigen represents a useful target for active and passive immunotherapy because of its high frequency in melanoma lesions, its limited heterogeneity in melanoma lesions, its high density on melanoma cells, and its restricted distribution in normal tissues (for review, see 10). Fourth, we have availability to use the mouse antiidiotypic MAb MFI 1-30 to an idiotope within the antigen-combining site of the syngeneic anti-HMW-MAA MAb 225.28. This antiidiotypic MAb bears the mirror image of HMW-MAA, because it induces anti-HMW-MAA antibodies in allogeneic and xenogeneic combinations (Chattopadhyay, P., S. V. Kaveri, J. Rosenberg, N. Byars, J. Starkey, S. Ferrone, and S. Raychadhuri. Submitted for publication.) The aim of this paper is to describe the results of two clinical trials with anti-1. Abbreviations used in this paper: HMW-MAA, high-molecularweight-melanoma-associated antigen; PBS-T20, PBS supplemented with 0.05% Tween 20; TAA, tumor-associated antigen.

An Anti-Idiotype Vaccine Elicits a Specific Response to N-Glycolyl Sialic Acid Residues of Glycoconjugates in Melanoma Patients

“…The characteristic of generating Ab3 Abs that share idiotopes with P3 mAb (Ab1) has been a common feature observed in mice (18), rabbits, and monkeys immunized with 1E10 mAb (our unpublished observation). The capacity to induce this kind of Ab3 has also been reported by other groups using different anti-Id mAbs (41)(42)(43)(44), indicating the capacity of anti-Id mAbs to generate "true" Ab3 Abs (Ab3, Idϩ).…”

Human High Molecular Weight Melanoma-Associated Antigen Mimicry by Mouse Anti-Idiotypic Monoclonal Antibody MK2-23: Enhancement of Immunogenicity of Anti-Idiotypic Monoclonal Antibody MK2-23 by Fusion with Interleukin 2

“…Several types of TAA mimics have been used. They include xenogeneic TAA (2,3), which display a high degree of amino acid sequence homology with that of the targeted TAA, peptide mimics (4,5), and anti-idiotypic antibodies (6)(7)(8)(9)(10)(11), both of which display structural homology with the nominal TAA in most cases. Thus far, anti-idiotypic antibodies have been among the most frequently used mimics to implement active specific immunotherapy of malignant diseases.…”

“…Thus far, anti-idiotypic antibodies have been among the most frequently used mimics to implement active specific immunotherapy of malignant diseases. TAA-specific immunity elicited by anti-idiotypic antibodies has been shown to exert beneficial effects on the clinical course of several malignant diseases (6)(7)(8)(9)(10)(11)(12).…”

“…Like other self-TAA, HMW-MAA is not immunogenic in hosts with constitutive expression of this antigen (13). To overcome unresponsiveness to this antigen, we have immunized melanoma patients with the anti-idiotypic mAb MF11-30 and MK2-23, which mimic the antigenic determinants defined by anti-HMW-MAA mAb 225.28 and 763.74, respectively (6,7). In agreement with results obtained in preclinical models (14), we have showed that conjugation of mAb MK2-23 with keyhole limpet hemocyanin (KLH) and coadministration with Bacillus Calmette-Guerin (BCG) as an adjuvant is required to elicit HMW-MAA-specific anti-antiidiotypic antibodies in melanoma patients.…”

“…Lyophilized, recombinant human IL-2 (Proleukin/Aldesleukin; specific activity: 3 Â 10 6 Cetus units/mg; Chiron Corp., Emeryville, CA) was reconstituted in sterile Milli-Q water to a concentration of 200 Ag/mL, aliquoted, and stored at À80jC until use. Directly before injection, this stock solution was further diluted to the working concentration in 5% dextrose solution.…”