Abstract
An efficient method was developed for the synthesis of a GM2 derivative suitable for the conjugation with various biomolecules. This GM2 derivative was covalently linked to keyhole limpet hemocyanin (KLH) and monophosphoryl lipid A (MPLA) to form novel therapeutic cancer vaccines. Immunological evaluations of the resultant conjugates in mice revealed that they elicited robust GM2-specific overall and IgG antibody responses. Moreover, the GM2-MPLA conjugate was disclosed to elicit strong immune responses without the use of an adjuvant, proving its self-adjuvant property. The antisera of both conjugates showed strong binding and mediated similarly effective complement-dependent cytotoxicity to GM2-expressing cancer cell line MCF-7. Based on these results, it was concluded that both GM2-MPLA and GM2-KLH are promising candidates as therapeutic cancer vaccines, whereas fully synthetic GM2-MPLA, which has homogeneous and well-defined structure and self-adjuvant property, deserves more attention and studies.
Highlights
Among all TACAs identified so far, GM2 is especially attractive for cancer vaccine development[39] because: (a) GM2 is relatively cancer-specific and expressed by several types of tumors, including melanoma, sarcoma, and renal cancer;[40] (b) GM2-reactive antibodies have been shown to mediate cytotoxicities against GM2-positive human cancer cell lines in vitro;[41,42,43,44] (c) GM2 is comparatively immunogenic, as evidenced by the presence of low titers of natural anti-GM2 IgM antibodies in some cancer patients[44,45,46] and by the findings that immunization of
Melanoma patients with GM2 conjugates could elicit anti-GM2 antibodies;[43, 44] (d) the presence of GM2 antibodies in melanoma patients appears to be associated with improved survival and longer disease-free interval;[44] (e) no deleterious side effects associated with immune responses to GM2 have been observed yet[44]
It was disclosed further that the GM2-keyhole limpet hemocyanin (KLH) conjugate combined with QS-21 adjuvant could induce high titers of IgM and IgG antibodies in patients, this combination is in clinical trial to treat melanoma[44, 52, 53]
Summary
Zhifang Zhou[1], Satadru S. The GM2-MPLA conjugate was disclosed to elicit strong immune responses without the use of an adjuvant, proving its self-adjuvant property The antisera of both conjugates showed strong binding and mediated effective complement-dependent cytotoxicity to GM2-expressing cancer cell line MCF-7. Based on these results, it was concluded that both GM2-MPLA and GM2-KLH are promising candidates as therapeutic cancer vaccines, whereas fully synthetic GM2-MPLA, which has homogeneous and well-defined structure and self-adjuvant property, deserves more attention and studies. Immunological responses of mice to the GM2-MPLA conjugate and GM2-KLH conjugate were evaluated and compared, so were the abilities of their antisera to bind to and kill cancer cells
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