The hunt for new therapeutics is daunting. Beyond the initial matchmaking of drug candidate and cellular target comes a string of hurdles—some sequential and many parallel—that include preclinical testing, formulation, manufacturing, stability, toxicology and clinical confirmation. As our knowledge of the myriad physiological pathways regulating the ocular surface has expanded, the number of potential targets for therapeutic intervention has grown. But the goal is not simply to accumulate prospects, but rather to identify and develop new treatments that address unmet needs.
In ocular allergy, we are well-served by the currently available cadre of antihistamines, anti-inflammatories and mast cell stabilizers, yet there remains a significant need for therapies that can alleviate chronic allergy and ocular inflammation. Most anti-allergic drugs target the mast cell and its chief minion histamine, but these cells are only one step in the ocular allergic cascade, and their activation frees a kaleidoscope of allergic mediators in addition to histamine. Many of these are molecules that we’ve examined over the years, while others, including those derived from neighboring tissues, have come to our attention only recently. This month we survey findings on new potential targets for therapeutic treatment of ocular allergy.
Mast Cells: An Allergic Nexus
Mast cells have been the target for most allergic therapies because of their role in the response to allergen exposure.
When mast cells are activated by binding of the complex of allergen, specific IgE and IgE receptors (FcεRs) expressed on the mast cell surface, a cascade of cellular events is initiated that includes the release of pre-formed allergic mediators and the synthesis of additional lipid-derived signaling compounds. At this point it may seem self-evident that since mast cells elicit allergic responses, and mast cells release histamine, histamine must be responsible for the allergic response. But this hadn’t been established when we began looking at histamine levels in tears and the association between those levels and ocular allergic disease.
In addition to histamine, mast cells package and secrete proteoglycans, various hydrolases and signaling molecules, including interleukins, tumor necrosis factor and platelet activating factor.
Mast Cell Targets
In previous installments of Therapeutic Topics, such as the May 2013 column, we discussed the importance of a number of protein kinases as potential targets for allergic therapy. Allergen cross-linking of the FcεRIs leads to activation of a series of kinases that provides the link between allergen and mast cell degranulation and activation.
Lipid-derived signaling molecules include prostaglandins, leukotrienes and PAF. Compounds that block cyclooxygenase, such as ketorolac or other NSAIDs, have been used in chronic allergy as steroid-sparing compounds, and they have demonstrated some efficacy, especially in VKC.
Studies dating back a decade or more demonstrated that PAF is chemotactic for eosinophils, and that this PAF-mediated chemotaxis has been shown to contribute to the chronic phase of allergic rhinitis and conjunctivitis.
Tackling Allergic Inflammation
A significant part of perennial and chronic allergy is ocular inflammation and the associated infiltration of inflammatory cell types into the ocular surface environment. Established mast cell pre-formed mediators such as TNF-α are thought to be involved in this process as either direct chemo-attractants or as instigators of inflammatory cell recruitment. Recent studies of TNF-α in pre-clinical models of ocular inflammation suggest that topical use of inhibitors can reduce both inflammatory cell recruitment and production of inflammatory cytokines such as IL-6.
Yet another approach to inflammation involves intervention beyond the mast cell. A key cytokine in inflammatory signaling is thymic stromal lymphopoietin, an epithelial cell-derived molecule that acts to shift adaptive responses toward a sensitized, allergic phenotype.
Monoclonals as Topicals?
Among current therapies, mast cell stabilizers such as pemirolast act at one of the earliest points in the allergic cascade, disrupting the linkage between FcεRI activation and mast cell degranulation.
As in other disorders, use of mAbs targeting other candidates for allergic intervention—interleukins or interleukin receptors, for example—will sink or swim based upon issues of pharmacokinetics. Even monovalent antibody fragments are extremely large molecules by pharmaceutical standards, and wouldn’t be expected to appreciably penetrate ocular tissues when applied topically. Despite this, a number of published studies have provided encouraging evidence that topically applied mAbs can have a therapeutic impact on the ocular surface. In several recent trials employing the topical VEGF inhibitors ranibizumab or bevacizumab as a treatment for corneal neovascularization, both treatments were able to reduce vascular proliferation.
Like the Japanese Camellia leaves that are used to make tea (and potentially, Syk inhibitors), another potential anti-allergic comes from an unlikely place: the kitchen. It turns out that turmeric roots, members of the ginger family that are commonly used as spices (especially in Indian foods) are also the source for curcumin, a polyphenol compound with multiple therapeutic applications. Among these is an ability to suppress responses to allergen challenge in a mouse model of allergic conjunctivitis.
It seems that we don’t have to look too far to find many potential targets for new therapies to treat ocular allergies, but as always, the real effort comes in sorting the true contenders from the false pretenders. Still, it’s encouraging to see that many of the newest treatment candidates have shown the promise of addressing our biggest current unmet need: chronic allergic conjunctivitis.
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Dr. Gelfman is senior director of Pre-Clinical and Translational Services at Ora, Inc. Dr. McLaughlin is a medical writer at Ora Inc.