RT Journal Article
SR Electronic
T1 Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.19.911941
DO 10.1101/2020.01.19.911941
A1 Yu Rebecca Miao
A1 Kaushik N. Thakkar
A1 Jin Qian
A1 Mihalis S. Kariolis
A1 Huang Wei
A1 Saravanan Nandagopal
A1 Teddy Yang
A1 Anh N. Diep
A1 Gerald Maxwell Cherf
A1 Yu Xu
A1 Eui Jung Moon
A1 Yiren Xiao
A1 Haizea Alemany
A1 Tianer Li
A1 Wenhua Yu
A1 Bo Wei
A1 Erinn B. Rankin
A1 Amato J. Giaccia
YR 2020
UL http://biorxiv.org/content/early/2020/01/20/2020.01.19.911941.abstract
AB Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have improved for a number of solid tumors. Unfortunately, ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB) with reported low patient response rates. Using IHC staining, we find that PD-L2 is highly expressed in ovarian cancers and other malignancies with sub-optimal response to ICB, and is expressed at low levels in cancers responsive to ICB. Based on this observation, we hypothesized that the elevated expression of PD-L2 produced by both tumor and surrounding stromal cells contributes to immune-suppression. Since PD-L2 has been reported to have a 6- to10-fold higher native binding affinity to PD-1 compared with PD-L1, we hypothesized that high levels of PD-L2 can lead to insufficient blockade of the PD-1 signaling pathway. To overcome the immune repressive activity of PD-L2, we engineered a soluble PD-1 decoy molecule (sPD-1 mutant) that binds and neutralizes both PD-L1 and PD-L2 with a 10,000- and 200- fold improvement in binding affinity, respectively, when compared to wild-type binding to these same molecules. Such enhancement in binding affinity is facilitated by amino acid mutations both within and outside of the binding interface. Furthermore, this high affinity sPD-1 mutant molecule demonstrates superior in vivo efficacy in multiple cancer models including ovarian cancer where PD-L2 is highly expressed on the cell surface.One Sentence Summary Dual Inhibition of PD-L1 and PD-L2 using an affinity enhanced sPD-1 decoy molecule delivers superior antitumor activity when compared with αPD-1 and αPD-L1 antibodies in ovarian cancer.