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

Abstract

Fully synthetic carbohydrate-based cancer vaccine is an attractive concept, while an important topic in the area is to develop proper vaccine carriers that can improve the immunogenicity and other immunological properties of tumor-associated carbohydrate antigens (TACAs). In this context, four monophosphoryl derivatives of Neisseria meningitidis lipid A were synthesized via a highly convergent and effective strategy and evaluated as vaccine carriers and adjuvants. The conjugates of these monophosphoryl lipid A (MPLA) derivatives with a modified form of the sTn antigen were found to elicit high titers of antigen-specific IgG antibodies, indicating T cell-dependent immune response, in the absence of an external adjuvant. It was concluded that MPLA’s could be utilized as potent vaccine carriers and built-in adjuvants to create fully synthetic self-adjuvanting carbohydrate-based cancer vaccines. The lipid composition and structure of MPLA were shown to have a significant influence on its immunological activity, and among the MPLA’s examined, natural N. meningitidis MPLA exhibited the most promising properties. Moreover, Titermax Gold, a conventional vaccine adjuvant, was revealed to inhibit, rather than promote, the immunological activity of MPLA conjugates, maybe via interacting with MPLA text goes here.

Carbohydrate‐based vaccines for oncotherapy

“…And the application of Titermax Gold, an external adjuvant, even reduced the immune responses to the MPLA conjugates . Simultaneously, they synthesized cancer vaccines with modified STn antigens conjugated to MPLA derivatives . After immunizing mice in the absence of external adjuvant, high titers of antigen‐specific IgG antibodies were introduced .…”

“…Simultaneously, they synthesized cancer vaccines with modified STn antigens conjugated to MPLA derivatives . After immunizing mice in the absence of external adjuvant, high titers of antigen‐specific IgG antibodies were introduced . Recently, a structurally defined glycoconjugate vaccine composed of Globo‐H and MPLA was fully synthesized, which induced significantly faster and stronger IgG1 antibody and T‐cell‐dependent immunity than the Globo‐H–KLH .…”

Progress in the synthesis and biological evaluation of lipid A and its derivatives

“…) carrying symmetric 2‐ N /3‐ O‐ and 2′‐ N /3′‐ O‐ lipids of varied chain length and structure. These MPLA derivatives were employed to systematically study the SARs of MPLA, such as how the lipid chain length and structure may affect the immunostimulatory and adjuvant activity of MPLA, to discover optimized vaccine carriers and adjuvants …”

“…To optimize MPLA as a vaccine carrier, Guo and co‐workers prepared several N. meningitidis MPLA derivatives 147 – 150 (Fig. ), which contained different lipids, and studied their SAR in the form of NPhAcsTn conjugates 240 – 243 . Following the above‐mentioned synthetic strategy for 229 , 147 – 150 were converted into active esters 235 – 238 , which were coupled with NPhAcsTn 239 (Scheme ).…”

Expression and functional evaluation of biopharmaceuticals made in plant chloroplasts

“…Similarly, hyper-phosphorylation of tissue factor prevents its interaction with other hemostatic proteins and interferes with the thrombin formation [44]. The extent of phosphorylation of the vaccine carrier, monophosphoryl lipid A also affects the toxicity and immunological activity [45]. The presence of phosphorylation activity in plant chloroplasts is evidenced by the identification of phosphor-proteins localized to the chloroplast and the corresponding kinases that perform phosphorylation functions.…”