Recombinant multi-target immunogens, built on multiple isomeric epitopes, that teach the immune system to neutralize the mediators behind chronic inflammation, pain and itch.
Active immunization: the animal’s own immune system makes the antibodies, against mediators produced by its own body, with a partial and reversible effect.
Xeptiva's immunogens are multi-target fusion proteins exhibiting multiple conformational isomers of a single peptidic chain. Immunogens lack the biological activity of targeted endogenous inflammatory mediators but share specific immunogenic structural epitopes.
Vaccination with Xeptiva's immunogens elicit antibodies in the host that recognize the targeted endogenous mediators involved in neurogenic inflammation, including growth factors, interleukins and/or neuropeptides.
Vaccines generate neutralizing antibodies against two or more endogenous inflammatory mediators underlying chronic inflammation, pain, itching, tissue damage, etc.
Vaccination reduced chronic inflammation eliciting a long-term therapeutic effect on symptoms allowing tissue regeneration, improving quality of life.
Pain in osteoarthritis and itch in atopic dermatitis persist long after the original injury or allergen, because the nervous system itself keeps the inflammation going. Sensitized sensory nerve endings release neuropeptides, chief among them Substance P, into the joint or the skin. Substance P dilates vessels, recruits immune cells and activates mast cells, which release more inflammatory mediators, NGF among them. NGF and IL-31 in turn sensitize the nerve endings further and drive more Substance P release.
This is neurogenic inflammation: a self-sustaining loop between nerves, mast cells and mediators that turns an acute response into a chronic disease. Current therapies act on one point of the loop. A monoclonal antibody blocks a single mediator; an anti-inflammatory drug dampens the response downstream. Xeptiva’s immunogens are designed against the loop itself, with antibodies against the mediator that sensitizes the nerve and against Substance P, the neuropeptide that carries the signal back to the tissue.
The immune system is trained not to respond to the body’s own proteins, and both components of Xeptiva’s immunogens are self-proteins: the mediator (canine NGF or canine IL-31) and Substance P, a neuropeptide whose sequence is conserved across mammals. Tolerance is broken without a carrier particle or a chemical conjugate. The two are expressed as a single recombinant fusion in E. coli and formulated without refolding, so the immune system meets them in a non-native form it does not treat as self, and the animal raises a polyclonal response against both.
The response is specific and measurable. In dogs, more than 90% seroconvert against the immunogen with the selected dose, and the antibodies cross-react with the animal’s own NGF or IL-31 and with Substance P.
Breaking tolerance raises one question before any other: whether immunizing an animal against its own mediator is safe. Across ten studies and about 250 dogs exposed to active product, no serious systemic event attributable to either immunogen has been recorded. The dominant event is a transient injection-site induration that resolves without treatment.
NGF, IL-31 and Substance P all have physiological roles in a healthy animal. The disease comes from their excess within the loop, not from their presence, so the goal is to bring that excess back toward the physiological range rather than to remove the molecules.
A monoclonal antibody blocks one mediator completely for as long as it is dosed. Active immunization raises a polyclonal response of finite magnitude against the mediator and Substance P, which peaks after priming, declines over months and is re-induced by a single booster. If a booster is withheld, antibody levels decline and the animal returns to baseline, with no exogenous protein to clear and no permanent change to the immune system. That reversibility is the safety margin.
Each product is a single recombinant protein. Xep01 and Xep02 constructs are expressed in E. coli and formulated without refolding, so that the immunogen presents several conformational isomers of the same peptide chain and shares structural epitopes with the native mediator without its biological activity.
The adjuvant is a commercial aqueous polymer gel, supplied under non-exclusive terms and already used in licensed veterinary vaccines. It was selected over oil emulsions for local tolerability and ease of formulation; the adjuvant concentration was set in the dose-ranging pilots together with the antigen dose.
Dose and adjuvant for each product were selected in a dose-ranging pilot in client-owned dogs by a pre-specified rule that weighed seroconversion at day 56 against the proportion of animals with injection-site reactions. The selected formulations are the ones that entered the controlled trials and the ones that transfer.
The antibody response follows the same curve in both products. A short priming course of three to four subcutaneous doses, two to three weeks apart, trains the immune system and builds immune memory. Antibody levels rise during the course and consolidate by day 42 to 56, when the clinical effect becomes measurable, and then decline slowly over months.
A single booster dose, given when clinical signs return, re-induces the response within one to two weeks, with a several-fold rise over the pre-booster level. This is a memory response: the animal does not need a new priming course. In the dogs followed to date, the interval between boosters has been four to six months, and in a cohort followed for two years, repeated boosters re-induced the response each time without escalation of local or systemic reactions. The booster is therefore given on demand, not on a calendar.
The clinical effect outlasts the antibody curve: animals stay improved for weeks after antibody levels start to fall. This is consistent with interrupting a self-sustaining loop rather than blocking a mediator moment to moment. Once neurogenic inflammation is quieted, it takes time to build up again.
Kinetics have been characterized for each component of the immunogen (the mediator and Substance P), for each dose group, after priming and after repeated boosters, with avidity and competition assays in the controlled trials. The curve is what makes the regimen predictable for a pivotal program: the windows for primary and consolidation endpoints come from the measured response, not from assumptions.
The immunogens are produced in recombinant expression systems, simpler and lower cost than mammalian cell culture.
One process serves every antigen on the platform: expression in E. coli, a single affinity capture step and formulation in the gel adjuvant, on standard recombinant fermentation equipment, with no refolding and no second chromatography step.
At 50 L scale one batch yields in the order of 200,000 single-dose vials, at a fully loaded cost per dose of about one US dollar including adjuvant, vial and release testing. Release methods cover identity, content and purity by SDS-PAGE, HPLC and mass spectrometry, endotoxin, host cell protein, residual DNA and sterility, plus a potency assay. Real-time stability at 2 to 8 °C is established at twelve months.
The platform was built to be reused. The construct logic, the expression system, the purification process and the adjuvant are the same for every program, so a new candidate goes from sequence to a pilot in the target species in months, without new process development. What changes from one program to the next is the mediator; everything around it is already built and already tested in animals.
That is how the pipeline grew beyond the two lead programs in dogs. Xeptiva has programs in development for chronic pain and inflammatory conditions in cats and horses, a second pain indication and a metabolic indication in dogs, and further small-animal candidates at the design stage. Each enters the same sequence as the first two: construct design, the same process, a pilot in the target species and a controlled proof of concept.
V Varela, M Costa, C Maciel, J Barbeito, E Barrera, E Gutierre, A Correa, M Elgue, S Carrasco, M Domínguez Larrosa, M Pereira, J Correa, N Crosignani, J Beckman, L Barbeito, E Trias
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