Human high molecular weight-melanoma associated antigen mimicry by mouse anti-idiotypic monoclonal antibodies MK2-23. Experimental studies and clinical trials in patients with malignant melanoma

Ferrone, Soldano; Chen, Z.J.; Liu, C.C.; Hirai, Satoshi; Kageshita, Toshiro; Mittelman, Abraham

doi:10.1016/0163-7258(93)90058-l

Cited by 25 publications

(14 citation statements)

References 62 publications

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“…Melanoma presents a heterogeneous pattern of various tumor markers, including melanocytic antigens and cancer testis antigens 8. Among them, HMW‐MAA9 is a melanoma marker of particular interest since ( i ) it is highly expressed at the surface of tumor cells, ( ii ) it has restricted distribution in normal tissues10, 11, 12 and ( iii ) the induction of specific humoral response to anti‐idiotypic anti‐HMW‐MAA MAb increases survival in patients with advanced melanoma 13, 14…”

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confidence: 99%

Non‐self‐discrimination as a driving concept in the identification of an immunodominant HMW‐MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients

Dummer

Mittelman

Fanizzi³

et al. 2004

Intl Journal of Cancer

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We analyzed the sera of patients with melanoma to define the human humoral autoantibody profile towards HMW-MAA. Computational proteome scanning using the non-selfdiscrimination principle as a guide led to the individuation of the low-similarity HMW-MAA 781 The vast majority of melanomas develop from cutaneous intraepidermal melanocytes either in normal skin or within melanocytic nevi and progress through radial and vertical growth phases. Cutaneous melanoma accounts for about 10% of skin cancer cases but 75% of skin cancer deaths. The incidence of cutaneous melanoma is rising steadily worldwide, and the median survival of patients with distant metastases remains Ͻ1 year. 1,2 Adolescent cases are on the rise too: the incidence of melanoma increased by 85% among 15-to 19-year-olds from 1973 to 1996. 3 This situation demands efforts to develop new biologic therapies. 4 A promising approach is the use of specific immunotherapy with peptide-based vaccine strategies. Conditio sine qua non to this goal is the identification of immunogenic tumor antigens, including antigenic peptides able to evoke humoral/cellular responses. [5][6][7] Melanoma presents a heterogeneous pattern of various tumor markers, including melanocytic antigens and cancer testis antigens. 8 Among them, HMW-MAA 9 is a melanoma marker of particular interest since (i) it is highly expressed at the surface of tumor cells, (ii) it has restricted distribution in normal tissues 10 -12 and (iii) the induction of specific humoral response to anti-idiotypic anti-HMW-MAA MAb increases survival in patients with advanced melanoma. 13,14 Given these premises, identification of the epitopic sequences of this proteoglycan MAA is of great interest for obtaining specific antibodies to activate the destruction of melanoma cells. However, the dimensions of the HMW-MAA molecule do not allow the definition of HMW-MAA conformational determinants and hamper the exact individuation of the immunogenic linear peptide portions of this antigen through the usual epitope mapping methodology.We have used computational biology to exploring TAA epitopes recognized by MAbs or polyclonal antibodies. [15][16][17][18] By measuring the antigenic peptide similarity to the host's proteome, we demonstrated that a low level of similarity is a necessary condition for a peptide to be immunogenic. Consequently, based on the assumption that antigenic motifs that are scarcely represented in human proteins may offer epitopic determinants unknown to the host, we searched for immunogenic epitopes of the human melanomaassociated chondroitin sulfate proteoglycan by, first, selecting for portions of the HMW-MAA not shared with the human proteome and, then, analyzing the low-similarity peptide reactivity pattern using sera from 26 melanoma patients.

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confidence: 99%

Non‐self‐discrimination as a driving concept in the identification of an immunodominant HMW‐MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients

Dummer

Mittelman

Fanizzi³

et al. 2004

Intl Journal of Cancer

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“…Its expression correlates with poor prognosis and balanced translocations into the mixed-lineage leukemia (MLL) gene [44,49]. MCSP expression remains unaffected by chemotherapeutic treatment [16]. Because of its high expression on tumor cells and its restricted distribution in normal tissues, this antigen has been used as a target for antibody-based immunotherapy in patients with melanoma.…”

Section: Introductionmentioning

confidence: 99%

A single chain immunotoxin, targeting the melanoma-associated chondroitin sulfate proteoglycan, is a potent inducer of apoptosis in cultured human melanoma cells

et al. 2008

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A recombinant immunotoxin was constructed by fusing a single-chain Fv (scFv) antibody fragment, specific for the melanoma-associated chondroitin sulfate proteoglycan (MCSP), to a truncated variant of Pseudomonas Exotoxin A (ETA'), carrying a C-terminal KDEL peptide for improved intracellular transport. The resulting immunotoxin, MCSP-ETA', induced antigen-specific, potent apoptosis in the cultured human melanoma-derived cell lines A2058 and A375M, and treatment with a single dose of the agent eliminated up to 80 % of these cells within 72 h. The dose needed for half-maximum killing (EC50) was approximately 1 nM for both cell lines. MCSP-ETA' also displayed cytotoxic activity against cultured primary melanoma cells from patients with advanced disease, with net cell death reaching up to 70 % within 96 h after treatment with a single dose of 14 nM. MCSP-ETA' induced cell death synergistically with Cyclosporin A (CsA), both in established human melanoma cell lines and cultured primary melanoma cells. The distinctive antigen-restricted induction of apoptosis and the synergy with CsA justify further evaluation of this novel agent with regard to its potential applications for the treatment of melanoma and other MCSP-positive malignancies.

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“…The reactivity patterns of mucosal melanoma lesions with the panel of anti-HLA Class-I MAbs are noteworthy, because of the potential role of these antigens in the interaction of melanoma cells with the host's immune system (for review, see Knuth et al, 1992) and because of the growing interest in the application of active specific immunotherapy in melanoma (for review, see Ferrone et al, 1993). Abnormalities in HLA Class-I antigen expression provide melanoma cells with a mechanism to escape from lysis by cytotoxic T cells and thus eliminate the beneficial effects of immunotherapeutic approaches which aim at generating cytotoxic T cells specific for MAA.…”

Section: Discussionmentioning

confidence: 99%

Antigenic profile of mucosal melanoma lesions

Kageshita

Kimura

Yoshii

et al. 1994

Intl Journal of Cancer

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Ten primary and 6 metastatic mucosal melanoma lesions were tested, utilizing the immunoperoxidase reaction with a panel of 26 monoclonal antibodies (MAbs). The latter included MAbs recognizing membrane-bound and cytoplasmic-melanoma-associated antigens, adhesion molecules and their receptors, and HLA Class-I and Class-II antigens. The melanoma lesions displayed differential reactivity with the panel of MAbs. Mucosal melanoma lesions differ from other types of melanoma in their antigenic profile, since they are the only type of melanoma to display a higher expression of p97 MAA, CEA-MAA and NGF-R in primary lesions than in metastatic ones. Furthermore, the pattern of HMW-MAA expression in mucosal melanoma lesions is different from that in nodular and uveal melanoma lesions and only partly resembles that observed in acral lentiginous melanoma lesions. Like other types of melanoma, mucosal melanoma lesions display a heterogeneous expression of HLA antigens, a selective loss of reactivity with some of the anti-HLA Class-I MAbs and a higher frequency of abnormalities in HLA Class-I antigen expression in metastatic than in primary lesions. Expression of HMW-MAA, 110-kDa MAA, p97 MAA, CEA-MAA, NGF-R and GD2 ganglioside in primary melanoma lesions was found to be associated with a poor prognosis. Although preliminary in nature, these results suggest that analysis of mucosal melanoma lesions with MAbs, in conjunction with information about the clinical course of the disease, will contribute to determine the biological and clinical significance of the distinct characteristics of the antigenic profile of mucosal melanoma lesions.

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Human high molecular weight-melanoma associated antigen mimicry by mouse anti-idiotypic monoclonal antibodies MK2-23. Experimental studies and clinical trials in patients with malignant melanoma

Cited by 25 publications

References 62 publications

Non‐self‐discrimination as a driving concept in the identification of an immunodominant HMW‐MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients

Non‐self‐discrimination as a driving concept in the identification of an immunodominant HMW‐MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients

A single chain immunotoxin, targeting the melanoma-associated chondroitin sulfate proteoglycan, is a potent inducer of apoptosis in cultured human melanoma cells

Antigenic profile of mucosal melanoma lesions

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