Abstract
Vaccines based on peptide mimics (mimotopes) of conformational tumor antigen epitopes have been investigated for a variety of human tumors including breast cancer, tumors expressing the carcinoembryonic antigen, B cell lymphoma, neuroblastoma, and melanoma. In our previous work, we designed a vaccine based on a mimotope of the high molecular weight-melanoma associated antigen (HMW-MAA) that elicited HMW-MAA-specific antibodies (Abs) with anti-tumor activity in vitro and in vivo. In this study, we aimed to identify mimotopes of additional distinct HMW-MAA epitopes, since they could be used to construct a polymimotope melanoma vaccine. For this purpose, random peptide phage libraries were screened with the anti-HMW-MAA monoclonal antibodies (mAbs) VT80.12 and VF1-TP43 yielding one peptide ligand for each mAb. Both peptides inhibited the binding of the corresponding mAb to the HMW-MAA. Furthermore, when coupled to the carrier protein keyhole limpet hemocyanin (KLH), both HMW-MAA mimotopes elicited peptide-specific Abs in rabbits or BALB/c mice, but only the mimotope isolated with the mAb VT80.12 elicited HMW-MAA-specific Abs and only in mice. However, the latter Abs had no detectable effect on HMW-MAA expressing human melanoma cells in vitro. These results describe limitations related to the phage display technique and emphasize the need to characterize the functional properties of the mAb utilized to isolate mimotopes of the corresponding epitopes.
Highlights
For at least two decades, the high molecular weight-melanoma associated antigen (HMW-MAA) has been the focus of several studies to implement effective immunotherapy for melanoma
The possibility that HMW-MAA represents a useful target to implement immunotherapy of melanoma has been initially suggested by the association between development of HMWMAA-specific antibodies (Abs) and statistically significant survival prolongation in patients with advanced melanoma immunized with a mouse anti-idiotypic monoclonal antibodies (mAbs) which mimics a HMW-MAA epitope [4,5]
We report the selection of mimotopes of additional HMW-MAA epitopes which are distinct from that defined by the mAb 225.28S and discuss limitations related to mimotope vaccines regarding their immunogenicity and antigenicity
Summary
For at least two decades, the high molecular weight-melanoma associated antigen (HMW-MAA) has been the focus of several studies to implement effective immunotherapy for melanoma. The possibility that HMW-MAA represents a useful target to implement immunotherapy of melanoma has been initially suggested by the association between development of HMWMAA-specific antibodies (Abs) and statistically significant survival prolongation in patients with advanced melanoma immunized with a mouse anti-idiotypic mAb which mimics a HMW-MAA epitope [4,5]. This possibility has been further supported by the results of several preclinical studies which have targeted HMW-MAA with Ab- and T cell-based immunotherapeutic strategies. In this study for the first time a syngeneic melanoma mouse model for HMW-MAA was used and novel information on the contribution of T cells to the therapeutic efficacy of HMW-MAA-specific immunity was provided
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