Treating Cancer with T Cell-Engaging Antibodies

Flavius Martin M.D.

Vice President Research, Amgen Inc.

For Internal Use Only. Amgen Confidential. 2

Tumor Cell Antigens:- Surface/Presented- Cell autonomous functions

T cells:- Response tuning- Effector function

T cell Tumor Immunotherapy Players

BiTE®

BiTE®

3

Engineering an Adapter From Two Monoclonal Antibodies

Tumor Cell-specificAntibody

T Cell-specific Antibody

VH

VL

VH

VL

Linker

BiTE®

Single-chain Antibody 1

BiTE® = Bispecific T Cell Engager

Single-chain Antibody 2

4

Any T Cell

Tumor Cell

CD3e

Do not Require MHC Class I andPeptide Antigen for Recognition by T Cell

Do not Require T Cell Clone With Specific T Cell Receptor

Can Make Any T Cell Recognize a Surface Antigen

TCRBiTE®

Antibody

BiTE® Antibodies May Circumvent Frequent Escape Mechanisms

XX

CD19EpCAMCEAPSMA

5

A549 Lung Cancer Cells Peacefully Coexist With T Cells

A549 Lung Cancer Cell:

T Cell Ratio = 1:1

Cancer Cell

RestingCD8+ T Cell

6

Each T Cell Can Kill Nearby Cancer Cell After BiTE® AMG 110 Is Added

Alive Cancer Cell

T Cell Apoptotic Cancer Cell

-EpCAM

-CD3

7

Kinetic Analysis of in-vitro BiTE® Reaction With Unstimulated T Cells

T cell potency increasesover time by 1-2 logs

AMG 330 = CD33/CD3-bispecific BiTE®; unstimulated human PBMC as effector cells at 10:1 ratio

AMG 330 [

10h

16h

22h

28h Complete lysis

Unstimulated T cells show lag phase beforethey start killing

8

Most Subpopulations of T Cells Can Contribute to Lysis by BiTE in vitro

T Cell Populations Studied MarkerRelative Potency of Redirected Lysis

CD8+ Bulk CD8+ +++

CD8+ Naïve CD28+ / CD45RA+ -/+

CD8+ EM CCR7- / CD45RA- ++++

CD8+ EMRA CD28- / CD45RA+ +++++

NKT Cells CD3+ / CD56+ ++

/g d T Cells CD3+ /a b- +

CD4+ Bulk CD4+ ++

CD4+ Naïve CD4+ / CD45RO- -/+

CD4+ EM CCR7- / CD45RA- +++

CD4+ EM+CM CD4+ / CD45RA- ++

CD4+ Naïve, Stimulated CD69, CD25 +++

CD4+ EM, Stimulated CD69, CD25 +++

Kischel, R. et al., poster at AACR 2009

9

Blinatumomab (AMG 103), a CD19/CD3-bispecific BiTE® Antibody• Murine antibody construct of 55 kDa produced by CHO cell-based

process

• CD19 target is diagnostic marker for B cell malignancies– 100% of ALL cases are positive for CD19

– Expressed on leukemic stem cells with self renewal capacity

– CD19 is activator of PI3 kinase

• Serum half life of AMG 103 is 1-2 hours continuous i.v. infusion using port/minipump

• Multiple clinical trials in adult and pediatric ALL patients; NHL experience

-CD19

-CD3

KD = 10-9 M

KD = 10-7 M

N

C

CD19-BiTE - Response and HSCT

n / N 95 % CI

Primary endpointCR/CRh during the first two cycles 81 / 189 43% 36–50

Exploratory endpointsMRD response during the first two cycles

CR/CRh 60 / 73 82% 72–90

CR, complete remission; CRh, complete remission with partial hematologicalrecovery of peripheral blood counts; MRD, minimal residual disease (< 10-4)

11

Activity of Blinatumomab in NHL Patients Is Dose-dependent (Phase 1 Study AMG 103-104)

0.51.5

5 15 30 60 90

Dose Levels Tested [µg/m2/Day]

Complete and Sustained B Cell Depletion

Peripheral T Cell Redistribution

Bone Marrow Clearance; First PR/CR

High RR

12x higher dose needed for tumor

12

Preliminary Learnings From Blinatumomab Monotherapy about BiTE® Modality

• Need only very low doses– High response rates in ALL patients at steady state serum levels of

0.5 to 1 ng/ml (<18 pM); cumulative doses of low milligrams per cycle

• Eliminates proliferating and nonproliferating target cells– Potential to eliminate dormant cancer stem cells

• Activity in many locations of body– Antitumor activity seen in blood, bone marrow, lymph nodes, spleen,

lymphoma tissue, liver tissue

• Activity in patients who have exhausted all established therapies, including rituximab regimen and SCT

• Activity in elderly and pediatric patients

• Activity in severly immunocompromised patients– Observed complete response in patients with low to undetectable

peripheral T cell counts

13

Other BiTE® Antibodies in Development

Clinical Phase 1:

• Solitomab (AMG 110: EpCAM) – Advanced solid tumors

• AMG 212 (BAY2010112: PSMA) – Prostate cancer

• AMG 211 (MEDI-565: CEA) – Advanced GI cancers

Pre-clinical:

• AMG 330 (CD33) – Acute myeloid leukemia (AML)

• Multiple myeloma BiTE --

• Solid tumor BiTE® –

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Extending Immunotherapy Response and Utility

Liquid tumors

Antigens

T cells

Solid tumors

Naked Antibodies

ADCs

BiTEsAntigensLonger half lifeCombos

Vaccines

BiTEsTumor antigens Biodistribution Combos

T cell modulators

ADCs

T cellular therapies

TCR-derived constructs -Intracellular antigens

T cellular therapies

Appendix

15

Confirmatory Open-label, Single-arm, Multicenter Phase 2 Study

*Only cycle 1, days 1 to 7: 9 μg/day

cIV, continuous intravenous; HSCT, hematopoietic stem cell transplantation

Scr

een

ing

an

d E

nro

llmen

t

Fo

llow

-up

(up

to 2

4 m

ont

hs)

HSCT Offered to Patients in CR/CRh

Blinatumomab28 μg/day*

cIV infusion

4 weeks on,2 weeks off

Up to 2 cycles

Primary endpoint

assessment

Blinatumomab28 μg/day

cIV infusion

4 weeks on,2 weeks off

Up to 3 cycles

Consolidation

Study EndpointsPrimary• CR/CRh during the first two

cycles

Secondary included• CR, CRh• Relapse-free survival• Overall survival• HSCT realization• Incidence of adverse events

Exploratory included• Minimal residual disease

response by PCR during the first two cycles

CR, complete remission; CRh, complete remission with partial hematological recovery of peripheral blood counts (platelets > 50,000/μl and ANC > 500/μl)

CD19-BiTE in ALL - Overall Survival

Overall SurvivalLandmark Analysis Day 77*

*After two treatment cycles

CR/CRh No CR/CRhN=79 N=50

Median OS, months 9.9 2.795% CI, months 6.8–NE 1.6–4.5

Overall Survival

0

0.2

0.4

0.6

0.8

1.0

Patients at Risk189 139 104 72 44 27 21 10 6 0

Pro

bab

ility

of O

vera

ll Surv

ival

Months0 2 4 6 8 10 12 14 16 18 20

0

0.2

0.4

0.6

0.8

1.0

Patients at Risk Months79 68 43 33 21 12 8 5 050 26 15 9 5 4 2 1 0

Pro

bab

ility

of O

vera

ll Surv

ival

0 2 4 6 8 10 12 14 16 18

N=189

Median OS, months 6.1

95% CI, months 4.2–7.5

NE, not estimable