Biologic medicine uses principles of what we know about normal immune responses to rebalance, restore, or stimulate a patient’s own immune system to fight disease. Biotherapeutics used in biologic medicine include immunostimulating cytokines (interferon), colony stimulating factors (erythropoietin) and therapeutic monoclonal antibodies (mAbs). Therapeutic mAbs can be used to block disease relevant proteins (cytokines, receptors) and target viruses or bacteria and aid in destruction and elimination of pathogens. A new biotherapeutic is in the pipeline and will have a specific application in veterinary dermatology.
Acquired knowledge about disease pathogenesis has resulted in the development of targeted therapies for chronic diseases for which the target antigen is now known. Therapeutic mAbs are designed to selectively target such proteins/antigens. These mAbs are created using recombinant DNA techniques. By use of recombinant DNA techniques one achieves therapeutic mAbs that are tolerated by the target species (humanized, caninzed, felinized) and can be administered directly to the patient.
What are therapeutic mAbs?
Therapeutic mAbs are given by injection, have a long half-life and are protected from destruction. Therapeutic mAbs are eliminated by intracellular catabolism within the lysosome where they are broken down into peptides or amino acids. These may be reused for synthesis of new proteins or renally excreted.
Examples of therapeutic mAbs
Examples of therapeutic mAbs in human medicine include omalizumab (Xolair) for allergic asthma. This mAb binds free IgE in plasma and intercellular fluid. Another, rituximab (Rituxan) targets CD20 on B lymphocytes and is used in the treatment of autoimmune disease and lymphomas. Therapeutic mAbs are well-tolerated in humans; the safety is attributable to specific targeting and no intracellular activity. Early human mAbs had a high proportion of mouse-derived sequences that were recognized as foreign. This resulted in immunogenicity, destruction of the mAb, decreased efficacy and side effects. Development of humanized and fully human mAbs addressed these problems. During the development of therapeutic mAbs for dogs, generation of fully caninized mAbs has been the goal.
Early examples of therapeutic mAbs for canines have been evaluated. An anti-IgE mAb has been shown to reduce house dust mite IgE hypersensitivity for a duration of five weeks in house dust mite sensitized beagles. This was done by use of mAbs that inhibit production of IgE via its promoting cytokines (IL4 and IL13), their cytokine receptors, or IgE itself. Therapeutic mAbs have also been shown to neutralize the pruritogenic IL-31 cytokine in dogs and reduce the pruritic response for three weeks after injection.
TJ Fleck et. al. (abstract 2015 NAVDF) identified and characterized a therapeutic mAb, ZTS-00103289, that neutralized IL-31 mediated pruritus in beagles. Recall that IL-31 has recently been shown to induce pruritus in multiple species. The increased expression of Il-31 is associated with severity of AD in humans. To evaluate the role of IL-31 in canine atopic dermatitis, a caninized mAb that inhibits IL-31 mediated cell-based signaling was identified and characterized. A subcutaneous dose of the mAb or an injection of placebo was administered at 1 mg/kg to the beagle dogs. Pruritus was assessed over time. Pruritus scores for mAb treated dogs were significantly lower than for placebo on day one and day 28. This study in beagle dogs supported the use of ZTS-00103289 subcutaneously to achieve a one-month duration of efficacy. A next step was to evaluate this in naturally occurring canine atopic dermatitis.
One had to first determine dose and duration of activity. A laboratory dose titration efficacy study with ZTS-00103289 was done by RR Walters et. al. (abstract, NAVDF 2015), wherein they used this caninized anti-IL-31 mAb in a canine beagle model of IL-31 induced pruritus. This study demonstrated the clear relationship between dose and duration of activity. In this study, the pruritogenic and pro-inflammatory cytokine IL-31 was administered to dogs to induce short-term pruritus. A single injection of ZTS-00103289 was then administered at various doses. Dogs then received IL-31 challenges. Results showed a significant reduction in pruritus with use of ZTS-0013289 and determined that free mAb ZTS-00103289 half-life of was 11.4 days. Anti-drug antibodies produced by the dog against the mAb were minimal and none persisted. The pharmacodynamic data concluded that a dose 2 mg/kg of ZTS-0013289 would result in a serum mAb concentration that remained above the EC50 for 28 days.
GM Michels et. al. (abstract, NAVDF 2015) reported a proof of concept efficacy and safety study of ZTS-00103289 anti-IL-31 mAb in the treatment of atopic dermatitis in client-owned dogs. ZTS-00103289 was dosed twice subcutaneously at 14-day intervals in dogs with AD. This was a masked placebo 42-day study including 78 dogs. Owner assessment of itch and dermatologist assessment of lesions were evaluated. Results showed that ZTS-00103289 treated dogs had significantly (>50%) greater reduction of pruritus from baseline in owner assessed pruritus scores compared to placebo on days two-42. Lesion scores improved 40% when evaluated at day 14 and day 28. No serious adverse events were reported. Antidrug-antibody levels showed no immunogenicity. The results of this study support the effectiveness and safety of ZTS-001-3289 for the treatment of canine atopic dermatitis.
Thus, with the advancement basic science and new knowledge about the molecules responsible for pruritus in dogs, a new biotherapeutic (ZTS-00103289) has being generated and tested in the laboratory and then in dogs with natural occurring disease. Based upon the studies reported, we anticipate this therapeutic mAb to be another safe and effective therapy we have to use in the management of dogs with canine atopic dermatitis.