肿瘤免疫治疗的单抗新药研发
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Key differentiation features: Unique SubQ administration Expect better efficacy and fast on-set of clinical response due to high binding affinity and small size of Dab, which could potentially be easier to penetrate tumor microenvironment,
SPR
Sample
CD137 14# mAb
Affinity matured
Ka 1.253E+4
3.383E+5
Kd 1.741E-4
9.072E-4
KD 2.992E-8
2.682E-9
5
0
0
10
20
30
40
Days
IFN-γ (ng/ml)
10 8 6 4 2 0 medium
CD137-14
Blood Vessel
Angiogenesis
inhibitors prevent
novel tumor
vasculature
formation
11
肿瘤免疫治疗的发展历程
肿瘤免疫治疗的多种方式
CAR-T BITES Imunocheckpoint antibody Tumor vaccine Cytokine Tumor Microenviroment
-Autoimmune CTAL-4, TNF, IL6, IL12/23, IL17,IL4/IL13,IL5, IgE…
-Metabolic/Endocrinology
RankL for osteoprosis, PCSK9 for high cholestol, cytokines for Diabetes
BMS663513 (full human mAb, IgG4)
PD1 PDL1 PDL1 OX40 CD137
|15
Company
BMS Pfizer BMS Merk
Roche/Genentech
State
Launched in 2011 Phase III, reactivated Launched Launched as 3rd line therapy
Linker selection
mAb engineering Conjugation
Toxin selection Toxin engineering
多种双功能抗体的构建方式
单抗药物简介
肿瘤免疫治疗单抗概述
康宁杰瑞相关研发
Alphamab Co Ltd. 2015
Targeted Cancer Drugs Chemotherapy
Humanized domain Ab
Mutant Fc
诱发肿瘤的免疫细胞侵润
IP status
PCT2013077453 PCT2013070342 CN200910136143.4 CN20140681422
22 Tumor-targeting Cytokine
|
Alphamab Co Ltd. 2015
mAb-cytokine 融合 – proof of concept
融合分子引起肿瘤消退和免疫记忆
mouse melanoma model B16 expressing EGFR
Day 0
7 10 13
免疫激活性抗体的开发
CD137 Agonist Ab Lead
relative tumor volume
6 with annuel sale over $6 billion in 2013
More than 70 mAb or related drugs are expected on the market in 2020
Market is forecasted to grow at a GACR ~8% in next
B
C
D
R^2
Plot#2 (RhCD137+C14mAb new : Concentration v... 0.122 2.16
36.4
2.27 0.988
20
__________
Weighting: Fixed
PBS
663513
15
CD137-14 mAb
10
RhCD137 binding
specificity
In vivo antitumor
Stability DSC
Tm=69℃
CD137-14 mab
LC: lambda
IgG4
Yield (transient) : 100ug/ml
T cell activation
Stability stress
Good stability at 45 degree In PBS at 10mg/ml for 30 days
肿瘤免疫治疗带来的突破
14
针对免疫检查点的单抗药物
Biotherapeutics
Ipilimumab (full human mAb, IgG1)
Target
CTLA4
Tremelimumab (full human mAb, IgG2) CTLA4
Nivolumab (full human mAb, IgG4)
Acknowledgement
康宁杰瑞
丁孚靶点
|20
S A Quezada1 and K S Peggs, BJC (2013) 108, 1560–1565
Alphamab Co Ltd. 2013
PD-L1 单域抗体开发
MoA: Humanized anti-Baidu NhomakorabeaD-L1 domain Ab
Status: P Expect FDA IND filing in 2Q2016 Expect CFDA IND filing in 1Q2016
PD1
Pembrolizumab (humanized mAb, IgG4)
MPDL3280A (human mAb, modified IgG1, crossspecies) MEDI4736 (humanized mAb, modified IgG1)
MEDI-6469 (humanized mAb)
Cancer Immunotherapy
Tumor targeted agents act
specifically on tumor Tucmelolsr cells
Immune cells
Immune stimulators or regulators to
promote anti-tumor immune response
-Tumor Immunotherapy
-Anti Infection - Virus, MDR bacterial
将来的重磅药物超过一半单抗药物
抗体药物的复杂结构
替代性抗体结构
7
Alternative Scaffold
|
Alphamab Co Ltd. 2015
抗体偶联药物-ADC
mAb selection
Graph#1 2 1.5
Specifically bind CD137, not bind other TNF family members OX40, CD27, GITR or B7 family members
1
0.5
0
0.01
0.1
1
10
100
1000
10000
x axis
4-P Fit: y = (A - D)/( 1 + (x/C)^B ) + D: A
~$215 billion in 2020
BioProcess Technology Consultants, Inc, 2015
3
Trends of mAb Development
|
Alphamab Co Ltd. 2015
单抗药物应用领域
-Classical Oncology targets – CD20,Her2, EGFR, Her3, VEGF…
CD137
T cell binding
anti-CD137 14# mAb SEC-HPLC
100
80
60
Ab dimers(%) 0d 10d 20d 30d
40
20
0
CD8
|26
26
肿瘤免疫治疗产品线
肿瘤免疫治疗的将来
CAR-T BITES Imunocheckpoint antibody Tumor vaccine Cytokine Tumor Microenviroment
肿瘤免疫治疗的单抗新药研发
徐霆 博士 苏州康宁杰瑞生物科技有限公司
单抗药物简介
肿瘤免疫治疗单抗概述 康宁杰瑞/丁孚相关研发
Alphamab Co Ltd. 2015
抗体药物的全球市场
47 mAb products on the market in US & Europe as of Nov., 2014
Phase III
MedImmune MedImmune BMS
Phase III Phase II Phase II
Alphamab Co Ltd. 2015
单抗药物简介 肿瘤免疫治疗单抗概述
康宁杰瑞相关研发
Alphamab Co Ltd. 2015
PD-L1 as validated 0nco-immuno Target
SPR
Sample
CD137 14# mAb
Affinity matured
Ka 1.253E+4
3.383E+5
Kd 1.741E-4
9.072E-4
KD 2.992E-8
2.682E-9
5
0
0
10
20
30
40
Days
IFN-γ (ng/ml)
10 8 6 4 2 0 medium
CD137-14
Blood Vessel
Angiogenesis
inhibitors prevent
novel tumor
vasculature
formation
11
肿瘤免疫治疗的发展历程
肿瘤免疫治疗的多种方式
CAR-T BITES Imunocheckpoint antibody Tumor vaccine Cytokine Tumor Microenviroment
-Autoimmune CTAL-4, TNF, IL6, IL12/23, IL17,IL4/IL13,IL5, IgE…
-Metabolic/Endocrinology
RankL for osteoprosis, PCSK9 for high cholestol, cytokines for Diabetes
BMS663513 (full human mAb, IgG4)
PD1 PDL1 PDL1 OX40 CD137
|15
Company
BMS Pfizer BMS Merk
Roche/Genentech
State
Launched in 2011 Phase III, reactivated Launched Launched as 3rd line therapy
Linker selection
mAb engineering Conjugation
Toxin selection Toxin engineering
多种双功能抗体的构建方式
单抗药物简介
肿瘤免疫治疗单抗概述
康宁杰瑞相关研发
Alphamab Co Ltd. 2015
Targeted Cancer Drugs Chemotherapy
Humanized domain Ab
Mutant Fc
诱发肿瘤的免疫细胞侵润
IP status
PCT2013077453 PCT2013070342 CN200910136143.4 CN20140681422
22 Tumor-targeting Cytokine
|
Alphamab Co Ltd. 2015
mAb-cytokine 融合 – proof of concept
融合分子引起肿瘤消退和免疫记忆
mouse melanoma model B16 expressing EGFR
Day 0
7 10 13
免疫激活性抗体的开发
CD137 Agonist Ab Lead
relative tumor volume
6 with annuel sale over $6 billion in 2013
More than 70 mAb or related drugs are expected on the market in 2020
Market is forecasted to grow at a GACR ~8% in next
B
C
D
R^2
Plot#2 (RhCD137+C14mAb new : Concentration v... 0.122 2.16
36.4
2.27 0.988
20
__________
Weighting: Fixed
PBS
663513
15
CD137-14 mAb
10
RhCD137 binding
specificity
In vivo antitumor
Stability DSC
Tm=69℃
CD137-14 mab
LC: lambda
IgG4
Yield (transient) : 100ug/ml
T cell activation
Stability stress
Good stability at 45 degree In PBS at 10mg/ml for 30 days
肿瘤免疫治疗带来的突破
14
针对免疫检查点的单抗药物
Biotherapeutics
Ipilimumab (full human mAb, IgG1)
Target
CTLA4
Tremelimumab (full human mAb, IgG2) CTLA4
Nivolumab (full human mAb, IgG4)
Acknowledgement
康宁杰瑞
丁孚靶点
|20
S A Quezada1 and K S Peggs, BJC (2013) 108, 1560–1565
Alphamab Co Ltd. 2013
PD-L1 单域抗体开发
MoA: Humanized anti-Baidu NhomakorabeaD-L1 domain Ab
Status: P Expect FDA IND filing in 2Q2016 Expect CFDA IND filing in 1Q2016
PD1
Pembrolizumab (humanized mAb, IgG4)
MPDL3280A (human mAb, modified IgG1, crossspecies) MEDI4736 (humanized mAb, modified IgG1)
MEDI-6469 (humanized mAb)
Cancer Immunotherapy
Tumor targeted agents act
specifically on tumor Tucmelolsr cells
Immune cells
Immune stimulators or regulators to
promote anti-tumor immune response
-Tumor Immunotherapy
-Anti Infection - Virus, MDR bacterial
将来的重磅药物超过一半单抗药物
抗体药物的复杂结构
替代性抗体结构
7
Alternative Scaffold
|
Alphamab Co Ltd. 2015
抗体偶联药物-ADC
mAb selection
Graph#1 2 1.5
Specifically bind CD137, not bind other TNF family members OX40, CD27, GITR or B7 family members
1
0.5
0
0.01
0.1
1
10
100
1000
10000
x axis
4-P Fit: y = (A - D)/( 1 + (x/C)^B ) + D: A
~$215 billion in 2020
BioProcess Technology Consultants, Inc, 2015
3
Trends of mAb Development
|
Alphamab Co Ltd. 2015
单抗药物应用领域
-Classical Oncology targets – CD20,Her2, EGFR, Her3, VEGF…
CD137
T cell binding
anti-CD137 14# mAb SEC-HPLC
100
80
60
Ab dimers(%) 0d 10d 20d 30d
40
20
0
CD8
|26
26
肿瘤免疫治疗产品线
肿瘤免疫治疗的将来
CAR-T BITES Imunocheckpoint antibody Tumor vaccine Cytokine Tumor Microenviroment
肿瘤免疫治疗的单抗新药研发
徐霆 博士 苏州康宁杰瑞生物科技有限公司
单抗药物简介
肿瘤免疫治疗单抗概述 康宁杰瑞/丁孚相关研发
Alphamab Co Ltd. 2015
抗体药物的全球市场
47 mAb products on the market in US & Europe as of Nov., 2014
Phase III
MedImmune MedImmune BMS
Phase III Phase II Phase II
Alphamab Co Ltd. 2015
单抗药物简介 肿瘤免疫治疗单抗概述
康宁杰瑞相关研发
Alphamab Co Ltd. 2015
PD-L1 as validated 0nco-immuno Target