Abstract: Provided herein is an immunocytokine comprising (i) an antigen binding protein (ABP) specific to a target protein; (ii) an IL-21 domain; and (iii) an IL-21R? mutein, wherein the IL-21R? mutein has a reduced binding affinity to the IL-21 domain compared to a wild-type IL-21R?. Further provided includes a method of using the immunocytokine to selectively activate an IL-21R? on a target cell, thereby enhance immune response or treat cancer.

Abstract: The present disclosure provides pharmaceutical compositions and compounds having dual agonist activity at the ? and ? opioid receptors. The agonist compounds of this disclosure can also provide GPCR functional selectivity, including selective activity in the Gi pathway. In some embodiments, the compounds of this disclosure are biased ?-opioid and/or ?-opioid receptor agonists that do not significantly recruit ?-arrestins, but can activate G-protein-dependent pathways, and thus can be administered without risk of significant undesirable side effects exhibited by conventional opioid receptor agonists. In some embodiments there is provided a substantially optically pure compound having dual agonist activity at the ? and ? opioid receptors.