Immunogenicity of a peptide‐based anti‐IgE conjugate vaccine in non‐human primates

Abstract

The anti‐human immunoglobulin E (IgE) monoclonal antibody, omalizumab (Xolair®, Genentech, South San Fransisco, CA), is effective in the treatment of poorly controlled moderate to severe allergic asthma and chronic idiopathic urticaria. It acts by specifically binding to the constant domain (Cϵ3) of free human IgE in the blood and interstitial fluid. Although efficacious, use of omalizumab is limited due to restrictions on patient weight and pre‐existing IgE levels, and frequent dosing (q2–4 weeks). A vaccine inducing anti‐IgE antibodies has the potential for similar clinical benefits with less frequent dosing and relatively lower cost of goods. We developed a vaccine containing two IgE peptide‐conjugates targeting the Cϵ3 domain of human IgE. As part of preclinical evaluation of the vaccine to optimize formulation and dose prior to initiating clinical studies, we evaluated the vaccine in non‐human primates, and demonstrate the induction of anti‐peptide antibodies that can bind to conformationally intact human IgE and are capable, at least in some animals, of substantial lowering circulating IgE levels.

Epitope targeting with self-assembled peptide vaccines

“…The first monoclonal Ab (mAb) approved for allergic asthma, omalizumab, recognizes a linear epitope on the Cε3 loop within the IgE heavy chain and prevents IgE receptor activation. 25,26 P10 peptide synthesized with the murine homolog of omalizumab’s epitope (DHPDFPKPIV) 18,26 at its C-terminus exhibited an average DLS diameter of ~15 nm (Supplementary Fig. 5).…”

“…A second therapeutic experiment targeted the mouse IgE heavy chain epitope analogous to omalizumab’s IgE-binding site. 18,25,26,32 Competition enzyme-linked immunosorbent assays (ELISAs) established that the Abs induced in mice specifically bound IgE with nanomolar avidity and reduced the concentrations of circulating free IgE. Moreover, this same Ab response effectively suppressed an IgE-mediated anaphylactic response.…”

“…Specificity of Ab binding and relative avidity to IgE was measured by competition ELISA. 48 Serial dilutions of murine IgE, IgG (Thermo Fisher, catalog #31903), or IgM (Southern Biotech, catalog #0101-01) were preincubated with antisera for 1 h and then added to wells coated with these Ab isotypes for an additional hour. Goat anti-mouse IgG Fc-HRP was used for detection at a dilution of 1:16,000.…”

“…7 There have been numerous clinical attempts to elicit therapeutic Ab levels to peptide B cell epitopes (BCEs) to treat other conditions, such as cancer, 15 Alzheimer’s disease, 16 and allergy. 17,18 Here we present a simple paradigm for eliciting immune responses to these BCEs by appending them to the termini of our carrier during SPPS. This method eliminates conventional conjugation reactions, which can negatively impact vaccine activity.…”

Use of nonhuman primates in obstructive lung disease research – is it required?

“…Human IgE-Fc has been shown to cross react with cynomolgus monkey effector cells (Saul et al, 2014), and the binding of human IgE to cynomolgus lung tissue potentially drives IgEmediated histamine release (Ishizaka et al, 1970;Wichmann et al, 2016). Later approved anti-IgE omalizumab showed binding to cynomolgus IgE (Fox et al, 1996;Meng et al, 1996), and efficacy assessment of a human-specific anti-IgE vaccine showed a reduction of circulating IgE, indicating the general suitability to test anti-IgE therapeutics in nonhuman primates (Weeratna et al, 2016). However, preclinical safety assessment of omalizumab in nonhuman primates revealed an age-dependent reduction of platelets, which was not detected in human patients, limiting the general transferability of data obtained in nonhuman primates (EMA, 2009a;Martin and Bugelski, 2012).…”