cd16 nk - 3 donors m
TRANSCRIPT
0 5 10 150
5
10
15
20
Time from dosing (d)
CD
3+C
D8
+ T
cell c
ou
nts
(fo
ld-c
han
ge f
rom
baselin
e)
0 5 10 150
2
4
6
8
Time from dosing (d)
CD
16
+ N
K c
ells
(fo
ld-c
han
ge f
rom
baselin
e)
0 5 10 150
5
10
15
Time from dosing (d)
Lym
ph
ocyte
s
(fo
ld-c
han
ge f
rom
baselin
e)
Potency-reduced candidate XmAb24306 promotes enhanced and sustained lymphocyte
expansion and has improved tolerability in monkeys compared to WT IL15/IL15R-Fc▪ IL15 is a highly active cytokine that stimulates NK and CD8+ T cells
▪ Unlike IL2, IL15 avoids biased Treg activation
▪ The IL15/IL15R complex is presented in trans to NK and CD8+ T cells
expressing IL2R and the common gamma chain (c)
▪ The recombinant IL15/IL15R heterodimer is highly active and
exclusively targets IL15 to IL2R/c expressing cells
▪ To create a long-acting IL15 therapeutic, we engineered IL15/IL15R
heterodimeric Fc-fusions using Xencor’s well-validated suite of Fc
domains
▪ Potency-reduced variants were created and found to promote superior
exposure and more pronounced pharmacodynamics in vivo
▪ Addition of our extended half-life Fc domain (Xtend®) further enhanced
in vivo half-life and provided even greater sustained exposure
© 2018 Xencor, Inc., Monrovia, CA 91016 USA
An IL15/IL15R heterodimeric Fc-fusion engineered for reduced potency
demonstrates an optimal balance of in vivo activity and exposure Matthew J. Bernett1, Rajat Varma1, Christine Bonzon1, Liz Bogaert1, Rumana Rashid1, Ke Liu1, Irene W.L. Leung1, Suzanne Schubbert1, Sung-Hyung Lee1, Daniel C. Kirouac2, Fei
Hua2, Nicole Rodriguez1, Yoon Kim1, Kendra N. Avery1, Connie Ardila1, Nargess Hassanzadeh-Kiabi1, Umesh S. Muchhal1, Seung Y. Chu1, Gregory L. Moore1, John R. Desjarlais1
1Xencor, Inc., 2Applied Biomath, LLC.
Introduction
SITC 2018
XmAb24306 is engineered for optimal activity with
reduced potency and extended in vivo half-life
Contact: [email protected]
IL15
IL2R
Common
chain
IL15R
(sushi)
IL2 and IL15 share IL2R and c receptor
interactions; rationale for design of IL15/IL15R-Fc
Structure of the IL15-receptor complex
IL15RIL2R
IL2Rc IL2R c
IL2 IL15
IL15 IL15R
Xencor
IL15/IL15R-Fc
RO-AUC
0 7 14 21 28 35 42 490
400
800
1200
1600
Time (d)
Mean
tu
mo
r vo
lum
e (
mm
3)
Day 7 Day 14 Day 21 Day 28100
101
102
103
104
105
106
107
CD
3+C
D8
+ c
ell c
ou
nts
(/45
l b
loo
d)
***
*** **
PBS only (no huPBMCs)
huPBMC + PBS
huPBMC + anti-PD1 (3 mg/kg)
huPBMC + XENP24045* (0.5 mg/kg) + anti-PD1 (3 mg/kg)
0 5 10 15-40
-30
-20
-10
0
10
Time from dosing (d)
Alb
um
in (
%ch
an
ge)
XmAb24306 (0.3 mg/kg)
XmAb24306 (0.6 mg/kg)
Pre
WT IL15/IL15R-Fc (0.3 mg/kg)
In vitro proliferation of huPBMCs
for 4 days
0.00
10.
01 0.1 1 10 10
0
1000
1000
0
1000
00
0
20
40
60
80
100
CD3+/CD8+/CD45RA- - 3 Donors
Concentration (nM)
Ki-
67
+%
WT IL15/IL15R-Fc
XmAb24306
0.00
10.
01 0.1 1 10 10
0
1000
1000
0
1000
00
0
20
40
60
80
100
CD16+ NK - 3 Donors
Concentration (nM)
Ki-
67
+%
WT IL15/IL15R-Fc
XmAb24306
~100-fold
reduced in
vitro
potency
▪ Potency-reduced IL15/IL15R(sushi domain) is attached to Xencor’s well-validated heterodimeric Fc
domain
▪ The Fc domain is further modified to eliminate FcR interactions and contains Xtend Fc technology to
promote longer half-life and extended pharmacodynamics (PD)
Structural model of IL15/IL15R-Fc
heterodimer
IL15 IL15R
(sushi)
0.001 0.01 0.1 1 10 100 1000 100000
20
40
60
80
Concentration (nM)
Ki-
67
+%
of
CD
8+ T
cells
Potency variant #3
XmAb24306
Potency variant #2 Potency variant #4
WT IL15/IL15R-Fc
Potency variant #1
Potency-reduced for optimal PK/PD
In vitro proliferation
of huPBMCs for 4
days
Fc Heterodimer
Xtend
0 2 4 6 8 100.001
0.01
0.1
1
10
100
Days post dose
Seru
m C
on
c. (
g/m
L)
Potency variant #4
Potency variant #2
Potency variant #1
WT IL15/IL15R-Fc
Potency variant #3
0 2 4 6 8 10 120.001
0.01
0.1
1
10
100
Days post dose
Seru
m C
on
c. (
g/m
L)
Potency variant #2 + Xtend
Potency variant #2
XmAb24306 (Xtend)
-5 0 5-5
0
5
XmAb24306 vs WT IL15/IL15R-Fc
Log2 (Fold change in gene expression) for XmAb24306
Lo
g2 (
Fo
ld c
han
ge in
gen
e
exp
ress
ion
) fo
r W
T IL
15
/IL
15R
-Fc
-5 0 5-5
0
5
XmAb24306 vs IL2
Log2 (Fold change in gene expression) for XmAb24306
Lo
g2 (
Fo
ld c
han
ge in
gen
e
exp
res
sio
n)
for
IL-2
-5 0 5-5
0
5
XmAb24306 vs IL15
Log2 (Fold change in gene expression) for XmAb24306
Lo
g2 (
Fo
ld c
han
ge in
gen
e
exp
res
sio
n)
for
IL
-15
▪ NanoString gene expression analysis of huPBMCs + XmAb24306, WT IL15/IL15R-Fc, IL2, or IL15 dosed at proliferation EC50 for 48 hr.
▪ XmAb24306 promotes similar gene expression compared to WT IL15/IL15R-Fc, IL2, and IL15
Summary
Potency reduction and Xtend technology combine to improve in vivo half-life in
monkeys
100
1000
10000
100000
CD
8+ T
ce
lls
(p
er
45
L b
loo
d) p ≤ 0.01
Potency-reduced IL15/IL15R-Fc combines productively with anti-PD1 in GVHD and anti-
tumor models
60
70
80
90
100
110
120
% In
itia
l B
od
y W
eig
ht
(D
ay 1
1)
PBMConly
αPD1(3 mg/kg)
XENP24045*(0.3 mg/kg)
Human CD8+ T cell counts GVHD is exacerbated
*XENP24045 is the non-Xtend analog of XmAb24306 used for mouse studies due to differences in human/mouse FcRn affinity of the Xtend Fc
αPD1(3 mg/kg)
+XENP24045* (0.3 mg/kg)
Potency reduction does not impact gene expression pattern when adjusted for dose
▪ We identified that IL15/IL15R-Fc variants engineered with substitutions to reduce potency demonstrated a dramatic inverse correlation of in vitro potency and in vivo half-life in monkeys
▪ The addition of Xencor’s Xtend Fc domain (enhanced affinity to FcRn @ pH 6) further increases half-life
▪ XmAb24306 was selected as the lead due to optimal combination of potency and half-life
RO-Max
▪ XmAb24306 consists of a reduced potency IL15/IL15R combined
with an extended half-life heterodimeric Fc domain
▪ XmAb24306 demonstrates more sustained in vivo lymphocyte
proliferation and improved tolerability in monkeys compared to WT
IL15/IL15R-Fc
Mechanism-based PK/PD model predicts optimal affinity to promote maximal PD
▪ Simulated RO-AUC predicts experimental PD
▪ Albumin decrease is best predicted by RO-Max
▪ Model demonstrates that reduced potency prolongs exposure
▪ Model demonstrates that an optimal Kd exists for maximal PD (T cell expansion)
Decreasing potency
(inactive)
+Xtend Fc
domain
Lead molecule
PBMConly
αPD1(3 mg/kg)
XENP24045*(0.3 mg/kg)
αPD1(3 mg/kg)
+XENP24045* (0.3 mg/kg)
Anti-tumor activity Peripheral T cell expansion
▪ XmAb24306 promotes maximal CD8, NK, and total
lymphocyte expansion with minimal albumin reduction
(measure of induced vascular leak)
▪ XmAb24306 appears to have superior therapeutic
index to WT IL15/IL15R-Fc
Pharmacodynamics (PD) of single-dose WT IL15/IL15R-Fc or XmAb24306 in cynomolgus monkeys
Up to 1000% increase in lymphocytes
p ≤ 0.001
p ≤ 0.001 p ≤ 0.01Anti-PD1 vsAnti-PD1 + XENP24045
*p ≤ 0.05p ≤ 0.01
*
** * *