がんに対する抗体療法の技術革新と新展開
Technological innovation of antibody therapy
for cancer and its perspectives
February 16, 2019

Shinsuke Iida, M.D.
Department of Hematology and Oncology
Nagoya City University Graduate School of Medical Sciences

Monoclonal antibodies (mAbs) for cancer therapy
Monoclonal Antibody, mAb:
⚫Recognizes a single antigen⚫Prepared from a single Ab producing plasmacell-derived hybridoma clone⚫Massively produced by biotechnology⚫Attacks just one antigen expressed on thecancer cells

Köhler G & Milstein C, 1975

Advances in molecular biology have made it possible to generatechimeric and humanized mAbs applicable to cancer treatment

Provided by Chugai Pharmaceutial Inc.

Mechanisms of action of immunotherapy modalities
in B-cell malignancies

CD47 - SIRPa(Don’t eat me signal)

5F9

Batlevo CL et al. Nat Rev Clin Oncol 2016; 13: 25-40.

Anti-tumor effect attributed by mAb
Direct anti-tumor effect・intracellular signal inhibition
・apoptosis induction

CDCADCC
CDCC
Antibody dependent cellular cytotoxicity (ADCC)
Complement dependent cellular toxicity (CDCC)
Complement dependent cytotoxicity (CDC)Monoclonal antibodies in Cancer treatment
CHOP + Rituximab

survival (%)

100

chemotherapy + Trastuzumab

100n= 202DLBCL

CHOP n= 197

50

235
Metastaticn=breastCancer

50
P = 0.007

n= 23400122436Mo00

N Engl J Med 346, 235-242 (2002).
100

100

30

4050

Metastatic colon cancer

Irradiation + Cetuximab
Locally advanced
radiotherapy
head & neck cancer

50

P < 0.001

n= 211n= 4120

P = 0.03

00

10

20

30

Mo

n= 213n= 403

IFL + placebo

20N Engl J Med 344, 783-792 (2001)

IFL + Bevacizumab5010Trastuzumab （anti-HER2)

Rituximab (anti-CD20)

survival (%)

P = 0.046

chemotherapy

40

Bevacizumab (anti-VEGF)
N Engl J Med 350, 2335-2342 (2004)

Mo01030

5070

Cetuximab (anti-EGFR)N Engl J Med 354, 567-578 (2006)

Mo

Engineered mAb by which enhances ADCC activity against cancer cells
Mogamulizumab targeting CCR4
expressed on ATLL cells

Asn297

N-terminal

Extracellulardomain

Enhanced ADCC effect bydefucosylated Fc regions
Shinkawa et al, J Biol Chem 2003;278:3466

CCR4 (CC chemokine receptor 4)

Cytolysis

100allo%auto
No effector cells

000.1

1.010

Anti-CCR4 mAb (mg/ml)

CCR4免疫染色

Ishida T, Ueda R, et al. Clin Cancer Res 2003; 9: 3625; 2004; 10: 7529.

Antibody-drug conjugate in Cancer treatment◼ Monomethyl aurinostatin (MMAC)
Brentuximab vedotin◼Indication: CD30 positive Hodgkin’s lymphoma and Anaplastic large cell lymphoma

Anti-CD30 mAb（cAC10）

linkerdrug（MMAE）

Deng C, et al. Clin Cancer Res 2012; 19: 22-27.

Brentuximab vedotin for Hodgkin’s lymphoma
relapsed after autologous stem cell transplantation
SGN035-0003 trial

CR 34%, Overall response rate 75%
Median duration of response: 6.7 mos（20.5 mos for the patients with CR）
Younes A et al. J Clin Oncol 30: 2183-9, 2012.

Mechanisms of action of immunotherapy modalities
in B-cell malignancies

Batlevo CL et al. Nat Rev Clin Oncol 2016; 13: 25-40.

Agonistic antibodies

Antagonistic antibodies

Immune-checkpoint blockade in Cancer treatment

Batlevo CL et al. Nat Rev Clin Oncol 2016; 13: 25-40.

Mechanisms of immune tolerance in lymphatic
tissues and tumor microenvironment

ICP; Immune checkpoint protein

Salama AKS & Moschos SJ Ann Oncol 2017; 28: 57-74.

Combination strategy to overcome immune tolerance

Progression-free survival

Median PFS: 6.9mo vs 11.5mo vs 2.9mo in Nivo, Nivo plus Ipi and Ipi arm
Larkin JV, et al. N Engl J Med 2015; May 31

Rates of grade ¾ treatment-related AEs reported in trialsof concurrent CTLA-4 and PD-1 pathway blockade
Immune-related AEs:
Spectrum of AEs with Ipi plus Nivo
was similar to monotherapy,but
Incidence of serious AEs was higher in
the Ipi plus Nivo arm compared withMonotherapy-treated patients.

irAE may occur early in the course oftherapy with combination treatment.

Salama AKS & Moschos SJ Ann Oncol 2017; 28: 57-74.

Mechanisms of action of immunotherapy modalities
in B-cell malignancies

Batlevo CL et al. Nat Rev Clin Oncol 2016; 13: 25-40.

T-cell-engaging antibodies for cancer

Batlevo CL et al. Nat Rev Clin Oncol 2016; 13: 25-40.

Bispecific T-cell engager (BiTE)

A. Generation, structure and B. mode of action of blinatumomab
Le Jeune C & Thomas X. Drug Design, Development and Therapy 2016;10:757-765.

Blinatumomab: Results of Randomized phase 3 study

CR with full hematologic recovery:
34% vs 16%, P < 0.001
6-mo Event-free survival:
31% vs 12%, HR 0.55 (0.43-0.71)
P < 0.001

Kantarjian H et al. N Engl J Med 2017; 376: 836-847.

Mechanisms of action of immunotherapy modalities
in B-cell malignancies

Batlevo CL et al. Nat Rev Clin Oncol 2016; 13: 25-40.

CAR-T therapy against CD19-positive lymphoid malignancies

Ledford H Nature 2014; 516: 156.
Maude SL, et al. Blood 2015; 125: 4017-4023.

Biology and clinical application of CAR T cells
for B-cell malignancies

1. Direct killing
2. Massive cytokine production
3. CAR-T cell proliferation
4. Crossing BBB↓
B cell aplasia
Cytokine release syndrome
neurotoxicity

Davila ML & Sadelain M Int J Hematol 2016; published online June 4

CD19-chimeric antigen receptor T-cell (CTL019) in DLBCL
N=15 (9 DLBCL, 2 indolent lymphoma, 4 CLL)
Conditioning regimen consisting of CPA of 120 or 60mg/kg and five day doses of Flu 25mg/m2followed by a single infusion of 1-5x106 CAR-T cells/kg
8/15: (53.3%) CR
4/7: DLBCL CR
4/15: PR
1/15: SD
2/15: NAToxicity:fevre, hypotension, delirium
Other neurological symptims
1 pt death 16 days after infusion

Tisagenlecleucel (JULIET)

CR 40%, ORR 52%

Kochenderfer JN et al. J Clin Oncol 2014; 33: 540-9.; Shuster SJ et al. NEJM 2019; 380: 45-56.

Today’s topics• Effective combination of immune checkpoint inhibitor
and way to overcome its resistance without
augmenting immune-related adverse events– Speakers: Drs. Wada H and Ohue Y• ADC technology can be applied to various cancertypes?
– Speakers: Drs. Nagai H, Agatsuma T and Bhadauria H• Activation of effector T-cells by BiTE technology ortransduction of CAR. What are the idealistic targets incancer therapy and this type of approach can beapplied to various tumors? --- Infrastructure in Japan– Speakers: Drs. Klinger M, Gilbert MJ and Hosen N

Thank you for your attention!

Department of Hematology and Oncology,Nagoya City University Graduate School of Medical Sciences