肿瘤免疫治疗的单抗新药研发

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
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Alphamab Co Ltd. 2015
-Autoimmune CTAL-4, TNF, IL6, IL12/23, IL17,IL4/IL13,IL5, IgE…
-Metabolic/Endocrinology
RankL for osteoprosis, PCSK9 for high cholestol, cytokines for Diabetes
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
Cancer Immunotherapy
Tumor targeted agents act
specifically on tumor Tucmelolsr cells
Immune cells
Immune stimulators or regulators to
promote anti-tumor immune response
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
|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-PD-L1 domain Ab
Status: P Expect FDA IND filing in 2Q2016 Expect CFDA IND filing in 1Q2016
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
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
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
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
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
~$215 billion in 2020
BioProcess Technology Consultants, Inc, 2015
3
Trends of mAb Development
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Alphamab Co Ltd. 2015
单抗药物应用领域
-Classical Oncology targets – CD20,Her2, EGFR, Her3, VEGF…
PD1
Pembrolizumab (humanized mAb, IgG4)
MPDL3280A (human mAb, modified IgG1, crossspecies) MEDI4736 (humanized mAb, modified IgG1)
MEDI-6469 (humanized mAb)
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 CyБайду номын сангаасokine Tumor Microenviroment
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
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
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
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,
Acknowledgement
康宁杰瑞
丁孚靶点
-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
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)