Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques.
Oxidation of LDL (oxLDL) is a crucial step in the development of cardiovascular disease. Treatment with antibodies directed against oxLDL can reduce atherosclerosis in rodent models through unknown mechanisms. We demonstrate that through a novel mechanism of immune complex formation and Fc-γ receptor (FcγR) engagement, antibodies targeting oxLDL (MLDL1278a) are anti-inflammatory on innate immune cells via modulation of Syk, p38 MAPK phosphorylation and NFκB activity. Subsequent administration of MLDL1278a in diet-induced obese (DIO) nonhuman primates (NHP) resulted in a significant decrease in pro-inflammatory cytokines and improved overall immune cell function. Importantly, MLDL1278a treatment improved insulin sensitivity independent of body weight change. This study demonstrates a novel mechanism by which an anti-oxLDL antibody improves immune function and insulin sensitivity independent of internalization of oxLDL. This identifies MLDL1278a as a potential therapy for reducing vascular inflammation in diabetic conditions.
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Shijie
S
Li
Paul
P
Kievit
Anna-Karin
AK
Robertson
Ganesh
G
Kolumam
Xiumin
X
Li
Karin
K
von Wachenfeldt
Christine
C
Valfridsson
Sherry
S
Bullens
Ilhem
I
Messaoudi
Lindsay
L
Bader
Kyra J
KJ
Cowan
Amrita
A
Kamath
Nicholas
N
van Bruggen
Stuart
S
Bunting
Björn
B
Frendéus
Kevin L
KL
Grove
Atherosclerosis; Diabetes; Inflammation; Nonhuman primate; Obesity; ox-LDL