Download - CD16 NK - 3 Donors m

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


CD

16

+ N

K c

ells

(fo

ld-c

han

ge f

rom

baselin

e)

0 5 10 150

5

10

15


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


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


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


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

*

** * *