K E Lewis1, M S Holdren2, M F Maurer1, S Underwood2, B Meengs3, S H Julien3, K A Byrnes-Blake2, J A Freeman2, T R Bukowski4, A C Wolf4, N B Hamacher4, M W Rixon3, S R Dillon1. 1. Discovery Biology Group, ZymoGenetics Inc. (a Bristol-Myers Squibb Company), Seattle, WA, USA. 2. Preclinical Development Group, ZymoGenetics Inc. (a Bristol-Myers Squibb Company), Seattle, WA, USA. 3. Protein Engineering Group, ZymoGenetics Inc. (a Bristol-Myers Squibb Company), Seattle, WA, USA. 4. Bioprocess Development Group, ZymoGenetics Inc. (a Bristol-Myers Squibb Company), Seattle, WA, USA.
Abstract
BACKGROUND: Overexpression or administration of interleukin 31 (IL-31) has been shown to induce a profound itch response in mice and dogs. The chronic pruritus observed in mouse IL-31 transgenic mice results in the development of skin lesions and alopecia through excoriation from excessive scratching, a condition similar to that observed in patients with atopic dermatitis (AD). OBJECTIVE: To test whether IL-31 induces pruritus in non-human primates and, if so, whether treatment with an anti-IL-31 neutralizing monoclonal antibody (mAb) can block the response. METHODS: A series of studies was conducted in cynomolgus monkeys to evaluate the itch response to recombinant cynomolgus IL-31 (cIL-31) administration. Three routes of cIL-31 administration (intravenous, intradermal, and subcutaneous) were evaluated. Subcutaneous treatment with a humanized anti-human IL-31 mAb cross-reactive to cIL-31 was subsequently tested for its ability to block the response to intradermal cIL-31 administration. RESULTS: Each route of cIL-31 delivery elicited a scratching response immediately after cIL-31 administration and lasted at least 3 h. Treatment with the IL-31 mAb inhibited the cIL-31-mediated scratching response in a dose-dependent manner. CONCLUSION: These results demonstrate that an IL-31 mAb can inhibit IL-31-mediated pruritus in vivo, and could be an effective therapy for pruritic skin conditions like AD where IL-31 upregulation may play a role.
BACKGROUND: Overexpression or administration of interleukin 31 (IL-31) has been shown to induce a profound itch response in mice and dogs. The chronic pruritus observed in mouseIL-31transgenic mice results in the development of skin lesions and alopecia through excoriation from excessive scratching, a condition similar to that observed in patients with atopic dermatitis (AD). OBJECTIVE: To test whether IL-31 induces pruritus in non-human primates and, if so, whether treatment with an anti-IL-31 neutralizing monoclonal antibody (mAb) can block the response. METHODS: A series of studies was conducted in cynomolgus monkeys to evaluate the itch response to recombinant cynomolgusIL-31 (cIL-31) administration. Three routes of cIL-31 administration (intravenous, intradermal, and subcutaneous) were evaluated. Subcutaneous treatment with a humanized anti-humanIL-31 mAb cross-reactive to cIL-31 was subsequently tested for its ability to block the response to intradermal cIL-31 administration. RESULTS: Each route of cIL-31 delivery elicited a scratching response immediately after cIL-31 administration and lasted at least 3 h. Treatment with the IL-31 mAb inhibited the cIL-31-mediated scratching response in a dose-dependent manner. CONCLUSION: These results demonstrate that an IL-31 mAb can inhibit IL-31-mediated pruritus in vivo, and could be an effective therapy for pruritic skin conditions like AD where IL-31 upregulation may play a role.
Authors: Angelica V Medina-Cucurella; Gary F Bammert; William Dunkle; Christopher Javens; Yaqi Zhu; Veronica T Mutchler; Janet T Teel; Caitlin A Stein; Steve A Dunham; Timothy A Whitehead Journal: Biochemistry Date: 2020-06-04 Impact factor: 3.162
Authors: Timothy J Fleck; Lori R Norris; Sean Mahabir; Rodney R Walters; Olivier Martinon; Steven A Dunham; Andrea J Gonzales Journal: Vet Dermatol Date: 2021-04-08 Impact factor: 1.867