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Abnova Investor Presentation 2019

Dec 12, 2019

52384_rns_2019-12-12_7ba906de-d50a-41df-964e-572333e54e0a.pdf

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亞諾法基因改造細胞治療介紹

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董事長 Wilber Huang 亞諾法生技

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免責聲明

本簡報及同時發佈之相關訊息包含財務、市場暨產品業務等預測性 資訊。本公司未來實際發生的營運結果及財務狀況可能與這些預測性資 訊所明示或暗示的預估有所差異，其原因可能來自於各種本公司所不能 掌控的風險。這些預估及展望的訊息，反應本公司截至目前為止對於未 來的看法，本公司並不負責隨時提醒或更新。

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“…… 未來 20-30 年，癌症治療將會有革命性的突破。

  • Joseph Jimenez, CEO of Novartis Forbes, 2014 May

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Almasbak H, et al., J Immuno Res 2016; 2016:5474602

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Prof. Tasuku Honjo
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US FDA recommended the approval of the first CAR-T cell therapy for B cell acute leukemia. (Novartis, 2017)

Cancer cells shown to be capable of hijacking PD-1 protein to evade destruction by immune system. (Honjo, 2002)

IL-2 based immunotherapy shown to reduce tumors in patients with melanoma and renal cell cancer.(Rosenburg, 1985)

2017

Prof. Tasuku Honjo 2002 2010 2000 2012 Dr. James Allison

1985

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Dr. Steven
Rosenberg
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Dr. Carl H. June
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1995

First child with leukemia treated with CAR-T cell therapy. (June, 2012)

CTLA-4 is found to inhibit the activity of T cells as a brake" of immune response. (Alison, 1995)

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1Immunotherapy timeline and progress https://www.cancerresearch.org/immunotherapy/timeline-of-progress 2FASEB: Cancer Immunotherapies: From Magic Bullets to Super T Cells http://faseb.org/Resources-for-the-Public/Breakthroughsand-Horizons-in-Bioscience.aspx

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  • Novartis –急性淋巴細胞白血病(ALL); FDA於2017年8月核

  • � NCI & Kite (acquired by Gileads) –瀰漫性大B細胞淋巴瘤(DLBCL); FDA於2017年10月核准

  • � UPenn, MSKCC, FHCRC & Juno (由Celgene投資)

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嵌合抗原受體T细胞治療(CAR-T細胞治療)

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四代CAR-T細胞治療發展歷程 增加CAR-T細胞的增殖，存活和細胞激素的產製

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Wang M, et al., Immunotherapy 2014; 6(12): 1265-1278

9

公司 產品 核心
技術		 適應症 進度 參考資料
Novartis Kymirah
(Tisagenlecle
ucel)		 CAR Lymphoma FDA
Approval		 https://www.us.kymri
ah.com
Kite/Gilead Yescarta
(Axicabtagen
e ciloleucel)		 CAR Lymphoma FDA
Approval		 https://www.yescarta
.com
Juno/Celgene JCAR CAR Lymphoma Phase I https://www.junothe
rapeutics.com/our-
pipeline/
Tessa
Therapeutics		 TT10 CTL Solid Tumor Phase III https://www.tessathe
rapeutics.com/pipeli
ne/
Iovance LN-144
LN-146		 TIL Solid Tumor Phase II http://www.iovance.c
om/clinical/c-144-
01-metastatic-
melanoma/
Atara Bio Tab-cel
(tabelecleucel)		 Alloge
neic
T Cell		 EBV
associated
hematologic
and solid
tumors		 Phase III http://www.atarabio.
com/pipeline/
Cell Medica CMD-003 TIL Lymphoma Phase II https://cellmedica.co
m/products/

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實體腫瘤細胞治療之挑戰

專一性 安全性 活性增強 微環境 T細胞存活率 運送 增生

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問題一 : 實體瘤缺乏腫瘤專一抗原標的、腫瘤抗原的下游調控 與腫瘤異質性

問題一:
實體瘤缺乏腫瘤專一抗原標的、腫瘤抗原的下游調控
與腫瘤異質性		 問題一:
實體瘤缺乏腫瘤專一抗原標的、腫瘤抗原的下游調控
與腫瘤異質性		 問題一:
實體瘤缺乏腫瘤專一抗原標的、腫瘤抗原的下游調控
與腫瘤異質性		 問題一:
實體瘤缺乏腫瘤專一抗原標的、腫瘤抗原的下游調控
與腫瘤異質性
Tumor-Associated Antigens
Cancer Antigens targeted by CARs
Breast cancer ERBB2 and MUC1
Cervical carcinoma CD44v6, CD44v7 and CD44v8
Gastrointestinalcancer CEA, EPCAM(also known as EGP2 and EGP40), TAG72 and KIT
Glioblastoma IL-13Rα2 and EGFR
Hepatocarcinoma ─
Lymphomas & Leukemia CD19, CD20, CD22, CD30, CD33,ҡ-LC, ROR1, CD38 and NKG2D
ligands
Melanoma CD3, HMW-MAA, MAGE1 and MAGEA3
Neuroblastoma CD2, CD171(L1CAM)and NCAM
Osteoscarcoma IL-11Rα
Ovarian cancer αFR and MUC1
Pancreatic cancer CEA
Prostate cancer PSCA, PSMA and TARP
Rhabdomyosarcoma Fetal acetylcholine receptor
Renal cancer CAIX
Tumor vasculature
VEGFR2 and PSMA
Universal
BBIR and FITC
Various tumors
TAG72, mesothelin, LeY, 5T4 oncofetal antigen, ERBB3, ERBB4 and
GP58		 Tumor vasculature VEGFR2 and PSMA
Universal BBIR and FITC
Various tumors TAG72, mesothelin, LeY, 5T4 oncofetal antigen, ERBB3, ERBB4 and
GP58

Keershaw M, et al., Nature Review 2013; August 13: 525-541

問題二 : 免疫抑制腫瘤微環境阻止T細胞深入滲透與毒殺異質性腫瘤細胞

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Scarfo I, et al., Journal for ImmunoTherapy of Cancer 2017 ; 5(28):1-8

14

問題三 :

CD19 CAR-T 治療相關的毒性反應

  • 細胞激素釋放綜合症(CRS) (腫瘤靶向毒性影響)

  • 與T細胞增生和活化效能相關

  • 與患者罹癌病狀程度相關

  • 觀察到在88%中; 有27%治療患者有低血壓與呼吸窘迫現象

  • 使用可逆IL-6 受體阻斷藥劑: Tocilizumab

  • 神經毒性(與細胞激素釋放綜合症同時發生)

  • 於數個CD19免疫治療臨床試驗中發現; NCI, CHOP/UPenn, MSKCC, Blinatumomab

  • 通常未經處理，完全解決

  • 慢性B細胞發育不良需替換Ig (靶向毒性腫瘤脫離) - 與T細胞增生和活化效能相關

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基因工程過繼T細胞免疫療法嚴重致命不良事件

Institution
TAA
Gene
transfer
Positive-receptor
(scFv or TCR)
Patient
populations
Lympho
depleting

Infused
cell doses

Time
Cause &
number of
 Institution
TAA
Gene
transfer
Positive-receptor
(scFv or TCR)
Patient
populations
Lympho
depleting

Infused
cell doses

Time
Cause &
number of
 Institution
TAA
Gene
transfer
Positive-receptor
(scFv or TCR)
Patient
populations
Lympho
depleting

Infused
cell doses

Time
Cause &
number of
Institution
TAA
Gene
transfer
Positive-receptor
(scFv or TCR)
Patient
populations
Lympho
depleting

Infused
cell doses

Time
Cause &
number of



regimens
(total)
deaths
Juno
Therapeutics
CD19
Retrovirus
scFv: 19z1-28ζ(2nd)
Relapsed or
refractory B-ALL
Cy + Flu
Unknown
Unknown
Neurologic
toxicity (3)
Chinese PLA
General
Hospital
CD20
Lentivirus
scFv: CAR.20-CD137ζ
(2nd)
Diffuse large B-
cell lymphoma
COD
107/kg
3 weeks
Massive
hemorrhage
of alimentary
tract (1)*
National
Cancer
Institute
HER2
Retrovirus
scFv: 4D5-CD8-28BBζ
(3rd)
Colon cancer
metastatic to the
lungs and liver
Cy 60 mg/kg for
2 days followed
by Flu 25 mg/m2
for 5 days
1010cells
5 days
CRS; Speculate
that off
tumor,
targeting lung
epithelial Cells
(1)
National
Cancer
Institute
MAGE-A3
/A12
Retrovirus
TCR: HLA-A0201-
restricted MAGE-A3
peptide: KMAELVHFL
Patient
5: Melanoma
8: esophageal
cancer
Cy 60 mg/kg for
2 days followed
by Flu 25 mg/m2
for 5 days
Patient 5: 7.9
×1010 cells
Patient 8:
6.1×1010 cells
Patient 5:
167 days;
Patient 8:
94 days
Neurologic
toxicity (2)
Washington**

Patient 1:
Patient 1 :Cy 60
mg/kg for 2
9
Patient 1: 4**

University;
University of
Pennsylvania
MAGE-A3
Retrovirus
TCR: HLA-A01-
restricted MAGE-A3
peptide: EVDPIGHLY
Melanoma
Patient 2:
Myeloma

days; Patient 2:
Melphalan at
200 mg/m2
followed HSCT
5.3×10 cells
2.4×109
cells.
days;
Patient 2: 5
days
Cardiovascular
toxicity (2)
University;
University of
Pennsylvania
MAGE-A3
Retrovirus
TCR: HLA-A01-
restricted MAGE-A3
peptide: EVDPIGHLY
Melanoma
Patient 2:
Myeloma

days; Patient 2:
Melphalan at
200 mg/m2
followed HSCT
5.3×10 cells
2.4×109
cells.
days;
Patient 2: 5
days
Cardiovascular
toxicity (2)

Mo Z, et al., J Cancer 2017; 8(9):1690-1703

16

問題四:

傳統腫瘤浸潤型淋巴細胞(TIL)治療需要從組織中分離T細胞， 而CAR-T細胞治療則以外邊血取代

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CAR-T治療針對實體瘤– 不完整的方案

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Jackson HJ, et al., Nat Rev Clin Oncol 2016; 13(6): 370-383

18

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方案一: 泛癌種抗原 結合低劑量化療與IL-12, 增強CD8+ T細胞中NKG2D的表現量 與泛腫瘤細胞中NKG2D配體的表現量

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Inducible
Constitutive
NKG2D
NKG2D
Expression
Expression
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CD8+ T 細胞中NKG2D 誘導、定位與實體 腫瘤抑制

  • 速溶艾黴素注射劑(Doxorubicin) 結合IL-12可誘導NKG2D專一表現於CD8+ T 細胞，其他免疫細胞並無發現有表現。

  • 速溶艾黴素注射劑結合IL-12誘導CD8+ T 細胞表現NKG2D可加強免疫細胞在實 體瘤中的定位。

  • 速溶艾黴素注射劑結合IL-12誘導CD8+ T 細胞表現NKG2D可抑制實體瘤生長與 代謝。

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Hu J, et al., Molecular Cancer 2014; 13(34): 1-13

實體腫瘤NKG2D 配體的誘導與表現

  • 隨著腫瘤惡性程度的增加，腫瘤中的NKG2D配體表現減少。

  • 化學治療劑可以體外而非體內誘導腫瘤細胞上的NKG2D配體。

  • 數種特定化學治療藥劑與IL-12的結合可以增加實體腫瘤中的NKG2D配體， 如: Doxorubicin, Cyclophosphamide, Cisplatin。

  • 速溶艾黴素注射劑結合IL-12誘導腫瘤專一的NKG2D配體表現且表現持久。

  • 在治療後正常組織，NKG2D配體不會被速溶艾黴素注射劑結合IL-12誘導表現。

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Hu J, et al., Cancer Immunol Res 2017; 5(4): 1-12

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方案二: IL12 表現於T細胞膜上

結合速溶艾黴素注射劑與attIL-12基因修飾T細胞，誘導T細胞深入 滲透至實體腫瘤中，克服腫瘤免疫抑制微環境

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Inducible T Infiltrating Lymphocyte
(iTIL)
attIL-12
(Membrane
Secreted IL-12 Anchored IL-12)
IL-
IL-12 IL-12
12
Receptor Receptor
T Cells T Cells
----- End of picture text -----

23

CD8+ T細胞深入滲透腫瘤毒殺腫瘤細胞

  • 速溶艾黴素注射劑或IL-12 單獨作用只能吸引CD8+ T 細胞至腫瘤邊緣。只有在速溶 艾黴素注射劑結合IL-12 可吸引CD8+ T細胞深入滲透腫瘤中心(直徑可達10mm) 。

  • 速溶艾黴素注射劑結合IL-12促進IFN-g表現，調節CXCL9和CXCL10的表達。

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Hu J, et al., Clin Cancer Res 2018; 24(2): 1-16

最新臨床前研究資料顯示: IL-12為抗癌標的關 鍵基因

  • IL-12 重組蛋白

  • 系統性尤以血液毒性反映顯著

  • 毒性作用與IFN-γ和TNF-α的二次產成有關

• IL-12 基因治療

  • 於腫瘤內注射IL-12質粒的基因轉殖效率低落

  • 腫瘤內電擊導入IL-12質粒的基因轉殖效率較高但無法適用於全身性腫瘤

  • -肌肉注射IL-12質粒搭配電極無法將IL-12定位於腫瘤位置

  • 組織TIL 結合誘導性IL-12 (Dr. Steve Rosenberg, NCI) - 肉瘤中TIL細胞治療因無法持續生成IL-12而造成反應短暫 - 血清中高含量的IL-12與臨床發現的IFN-g引發毒性相關

  • 周邊血TCR結合誘導性IL-12 (Dr. Steve Rosenberg, NCI) - 在肉瘤和黑色素瘤中T細胞受體對NY-ESO-1腫瘤抗原具有專一性

    • 在試驗開始數週後研究暫停，隨即終止。

  • 第四代CAR-T 細胞結合誘導性IL-12 (Dr. Brentgens, MSKCC)

  • 有分泌IL-12的MUC-16 CAR-T細胞可治療卵巢癌

25

方案三: 局限細胞因子引發的細胞毒性區域 速溶艾黴素注射劑直接促使IL-12局限於腫瘤中誘導IFN-g分泌免疫 細胞，減緩全身性IFN-g 反應效應與細胞激素釋放綜合症

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Zhu S W, et al., Clin Cancer Res 2007; 13(14): 4525-4260

26

速溶艾黴素注射劑局限強烈IL-12腫瘤內細胞免疫 反應，避免引起全身系統性影響

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Lasek W, et al., Cancer Immunol Immunother 2014; 419-435

27

方案四: attIL-12 基因修飾誘導型腫瘤浸潤淋巴細胞可抽取血液製備，無須 透過組織採集

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亞諾法與MD Anderson合作 全球專屬授權iTIL技術

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