Carbohydrate-Monophosphoryl Lipid A Conjugates Are Fully Synthetic Self-Adjuvanting Cancer Vaccines Eliciting Robust Immune Responses in the Mouse

Abstract

Tumor-associated carbohydrate antigens (TACAs) are useful targets in the development of therapeutic cancer vaccines. However, a serious problem with them is the poor immunogenicity. To overcome the problem, a monophosphorylated derivative of Neisseria meningitidis lipid A was explored as a potential carrier molecule and built-in adjuvant for the construction of structurally defined fully synthetic glycoconjugate vaccines. Some paradigm-shifting discoveries about the monophosphoryl lipid A (MPLA)-TACA conjugates were that they elicited robust IgG antibody responses, indicating T cell-mediated immunity, without an external adjuvant and that an external adjuvant, e.g., Titermax Gold, actually reduced, instead of promoting, the immunological activity of the conjugates. The induced antibodies were proved to bind selectively to target tumor cells. MPLA was therefore demonstrated to be a powerful built-in immunostimulant and adjuvant for an all new design of fully synthetic glycoconjugate cancer vaccines.

Synthesis and evaluation of monophosphoryl lipid A derivatives as fully synthetic self-adjuvanting glycoconjugate cancer vaccine carriers

“…Antibody titers were calculated from linear regression analysis of the curves of the optical density (OD) value against serum dilution number, and were defined as the dilution number yielding an OD value of 0.2. 34 …”

“…39,40 Therefore, all of the synthetic MPLA derivatives could act both as a vaccine carrier and as an adjuvant to effectively enhance the immunogenicity of sTnNPhAc and to efficiently promote T cell-dependent immune response toward TACAs. 18,34,41 This property of MPLA should be particularly useful for the design and development of new fully synthetic carbohydrate-based conjugate vaccines. Titermax Gold is a commercial adjuvant that is commonly used with vaccines such as carbohydrate-protein conjugates 42 to improve their immunogenicity.…”

“…33 The resultant conjugate alone induced promising immune responses in animals in the absence of any external adjuvant, suggesting that, as an immunostimulant, MPLA was functional not only as a vaccine carrier but also as a built-in adjuvant. 34 Inspired by this discovery, here we have designed and synthesized three other monophosphoryl analogs of the lipid A of N. meningitidis , containing lipids of different chain length and linkage as well as different patterns of lipidation (Figure 1). To investigate the immunological properties of these MPLA derivatives as vaccine carriers and adjuvants, we conjugated them with N -phenylacetyl sTn (sTnNPhAc), a modified TACA that is currently studied for anticancer vaccine development, 35 and examined in mouse the specific immune responses induced by the resultant MPLA-sTnNPhAc conjugates 3–6 (Figure 1).…”

Overview and Outlook of Toll-like Receptor ligand–antigen Conjugate Vaccines

“…Recently, Wang and colleagues reported the design of several TLR4 ligand-antigen conjugates and evaluated their immunological efficacy as cancer vaccines [68,69]. GM3, a TACA abundantly expressed by human melanoma as well as other tumor cells, was chemically conjugated to MPL (FiguRe 4).…”

Recent Development in Carbohydrate Based Anticancer Vaccines

“…Interestingly, although this construct lacks a peptide Th epitope, robust IgG3 antibody responses were observed, which reacted strongly with glycoengineered SKMEL-28 cancer cells. [150] The addition of an external adjuvant, i.e ., Titermax Gold, greatly reduced the immunological activity of the conjugates possibly due to the interaction between MLPA and Titermax Gold.…”