A Long-Acting PYY                         3–36                          Analog Mediates Robust Anorectic Efficacy with Minimal Emesis in Nonhuman Primates

Shamina M. Rangwala; Katharine D'Aquino; Yue Mei Zhang; Lindsay Bader; Wilson Edwards; Songmao Zheng; Annette Eckardt; Ann Lacombe; Rebecca Pick; Veronica Moreno; Lijuan Kang; Wenying Jian; Eric Arnoult; Martin Case; Celia Jenkinson; Ellen Chi; Ronald V. Swanson; Paul Kievit; Kevin Grove; Mark Macielag; Mark D. Erion; Ranabir SinhaRoy; James N. Leonard

doi:10.1016/j.cmet.2019.01.017

A Long-Acting PYY _3–36 Analog Mediates Robust Anorectic Efficacy with Minimal Emesis in Nonhuman Primates

Shamina M. Rangwala, Katharine D'Aquino, Yue Mei Zhang, Lindsay Bader, Wilson Edwards, Songmao Zheng, Annette Eckardt, Ann Lacombe, Rebecca Pick, Veronica Moreno, Lijuan Kang, Wenying Jian, Eric Arnoult, Martin Case, Celia Jenkinson, Ellen Chi, Ronald V. Swanson, Paul Kievit, Kevin Grove, Mark MacielagMark D. Erion, Ranabir SinhaRoy, James N. Leonard

Oregon National Primate Research Center

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

The gut hormone PYY _3–36 reduces food intake in humans and exhibits at least additive efficacy in combination with GLP-1. However, the utility of PYY analogs as anti-obesity agents has been severely limited by emesis and rapid proteolysis, a profile similarly observed with native PYY _3–36 in obese rhesus macaques. Here, we found that antibody conjugation of a cyclized PYY _3–36 analog achieved high NPY2R selectivity, unprecedented in vivo stability, and gradual infusion-like exposure. These properties permitted profound reduction of food intake when administered to macaques for 23 days without a single emetic event in any animal. Co-administration with the GLP-1 receptor agonist liraglutide for an additional 5 days further reduced food intake with only one animal experiencing a single bout of emesis. This antibody-conjugated PYY analog therefore may enable the long-sought potential of GLP-1/PYY-based combination treatment to achieve robust, well-tolerated weight reduction in obese patients.

Original language	English (US)
Pages (from-to)	837-843.e5
Journal	Cell Metabolism
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2019.01.017
State	Published - Apr 2 2019

Keywords

GLP-1
PYY
body weight
emesis
food intake
gastric bypass surgery
gut peptide hormone
obesity
tolerability

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2019.01.017

Cite this

Rangwala, S. M., D'Aquino, K., Zhang, Y. M., Bader, L., Edwards, W., Zheng, S., Eckardt, A., Lacombe, A., Pick, R., Moreno, V., Kang, L., Jian, W., Arnoult, E., Case, M., Jenkinson, C., Chi, E., Swanson, R. V., Kievit, P., Grove, K., ... Leonard, J. N. (2019). A Long-Acting PYY _3–36 Analog Mediates Robust Anorectic Efficacy with Minimal Emesis in Nonhuman Primates Cell Metabolism, 29(4), 837-843.e5. https://doi.org/10.1016/j.cmet.2019.01.017

A Long-Acting PYY _3–36 Analog Mediates Robust Anorectic Efficacy with Minimal Emesis in Nonhuman Primates . / Rangwala, Shamina M.; D'Aquino, Katharine; Zhang, Yue Mei et al.
In: Cell Metabolism, Vol. 29, No. 4, 02.04.2019, p. 837-843.e5.

Research output: Contribution to journal › Article › peer-review

Rangwala, SM, D'Aquino, K, Zhang, YM, Bader, L, Edwards, W, Zheng, S, Eckardt, A, Lacombe, A, Pick, R, Moreno, V, Kang, L, Jian, W, Arnoult, E, Case, M, Jenkinson, C, Chi, E, Swanson, RV, Kievit, P, Grove, K, Macielag, M, Erion, MD, SinhaRoy, R & Leonard, JN 2019, ' A Long-Acting PYY _3–36 Analog Mediates Robust Anorectic Efficacy with Minimal Emesis in Nonhuman Primates ', Cell Metabolism, vol. 29, no. 4, pp. 837-843.e5. https://doi.org/10.1016/j.cmet.2019.01.017

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abstract = " The gut hormone PYY 3–36 reduces food intake in humans and exhibits at least additive efficacy in combination with GLP-1. However, the utility of PYY analogs as anti-obesity agents has been severely limited by emesis and rapid proteolysis, a profile similarly observed with native PYY 3–36 in obese rhesus macaques. Here, we found that antibody conjugation of a cyclized PYY 3–36 analog achieved high NPY2R selectivity, unprecedented in vivo stability, and gradual infusion-like exposure. These properties permitted profound reduction of food intake when administered to macaques for 23 days without a single emetic event in any animal. Co-administration with the GLP-1 receptor agonist liraglutide for an additional 5 days further reduced food intake with only one animal experiencing a single bout of emesis. This antibody-conjugated PYY analog therefore may enable the long-sought potential of GLP-1/PYY-based combination treatment to achieve robust, well-tolerated weight reduction in obese patients.",

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