20240808_国联证券_医药生物行业深度研究：肿瘤免疫赛道谁能延续大单品传奇？_24页.pdf

glzqdatemark1|2024年08月08日|1/23 PD1/IL2 PD1/IL15 PD1/IL2 R-bias IBI363 PD1/IL15 ASKG315 ASKG915 SHR-1501 BD K SAC S0590521070002 WUCXwPrMmPrQoQmPmRpQnMaQdN7NsQmMtRrNfQmMvNlOpOtRaQrRvMwMtPsPMYtQqR 2/23|glzqdatemark2 1 2.0 DRG/DIP-2024.07.24 2 2024.07.20 PD1/PDL1 K 2023 250+PD1/IL-2R bias IL2 PD1/IL-2R-bias IL-2Rn 2018 BMS 36.5 Nektar IL-2 2019 25 Synthrox IL-2 THOR-707 IBI363 2024 ASCO IL-15 N-803 IL-15 IL-15 2024 4 ImmunityBio IL15/IL15R-Fc N-803 FDA(CIS)BCG(NMIBC)PD1/IL2 PD1/IL15 PD1/IL2 PD1/IL15 PD1/IL2 R-bias IBI363 PD1/IL15 ASKG315 ASKG915 SHR-1501 BD K EPS PE CAGR-3 XXXX XXXX XXXX XXXX XXXX XXXX-30%-17%-3%10%2023/7 2023/11 2024/3 2024/7 3002024年08月08日 3/23|PD1/PDL1 K 2023 250+1 PD1/IL-2R-bias BD IL-2Rn IBI363 2024 ASCO 2 IL-15 IL-15 2024 4 ImmunityBio IL15/IL15R-Fc N-803 FDA 3 PD1/IL2 PD1/IL15 PD1/IL2 R-bias IBI363 PD1/IL15 ASKG315 ASKG915 SHR-1501 BD K x913t0R9w0YvaP8iAPVUifC4iNkD3XJlIbfvIKRvuXLiCWpG7g/ndP41vvGHvMpJ 4/23|1.5 1.1.6 1.2.9 2.IL2.12 2.1 IL-2.13 2.2 PD1/IL-2R bias.15 3.IL15.18 3.1 IL15.18 3.2 IL15.20 4.PD1/IL2 PD1/IL15.22 5.22 1.6 2.7 3 FDA.8 4.10 5.11 6.11 7 IL-2R.12 8 IL2.13 9 IL2.14 10 IBI363.16 11 IBI363 vs K.16 12 IL-15.18 13 IL-15.19 14 N-803.19 15 IL15.21 16 ASKG315 ASKG915.21 5/23|1.2011 CTLA-4 PD-1 PD-L1 LAG3 FDA IL-2 IL15 T Sipuleucel-T 2015 FDA T-Vec 6/23|1 Cellular&Molecular Immunology The history and advances in cancer immunotherapy:understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications Yuanyuan Zhang 1.1 IC T CTLA-4 PD1/PD-L1 LAG-3 T ITIM TIGIT T-3 TIM-3 2,3-IDO SIRP 7/23|2 Signal Transduction and Targeted Therapy Immune checkpoint therapy for solid tumours:clinical dilemmas and future trends Qian Sun 1 CTLA-4 CTLA-4 T T CTLA-4 2 PD1/PDL1 PD-L1 PD-1/PD-L1 T 3 OpdualagLAG-3 APC MHC CD4 T 8/23|3 FDA FDA YERVOY()BMS CTLA-4 2011-03 RCC,CRC,HCC,NSCLC,MPM,EC 5%10mg/kg 5%KEYTRUDA()PD-1 2014-09 NSCLC,HNSCC,cHL,PMBCL,UC,MSI-H/dMMR,CRC,GC,EC,CC,MCC,RCC,EMC,TMB-H,cSCC,TNBC/OPDIVO()BMS PD-1 2014-12 BRAF BRAF V600 NSCLC,MPM,RCC,cHL,HNSCC,UC,CRC,HCC,EC,GC,GJC,EAC/TECENTRIQ()Roche PD-L1 2016-05 12 NSCLC,ES-SCLC,HCC,BAVENCIO()PD-L1 2017-03 12 UC,RCC MCC:UC:RCC IMFINZI()PD-L1 2017-05 12 NSCLC,ES-SCLC,BTC NSCLC SCLC/LIBTAYO()(Regeneron)PD-1 2018-09 CSCC BCC,NSCLC,CC 15%3-4/2%JEMPERLI(dostarlimab)GSK PD-1 2021-04 dMMR dMMR/3-4 2%OPDUALAG(BMS PD-1&LAG-3 2022-03 12 Imjudo AZ CTLA-4 2022-10 HCC NSCLC 9/23|Zynyz Retifanlimab Incyte PD-1 2023-03 MCC PD-1 2023-10 PD-1 2024-03 PD-(L)1(ESCC)Signal Transduction and Targeted Therapy Immune checkpoint therapy for solid tumours:clinical dilemmas and future trends Qian Sun ICB 10-30%1.2/1 2 1 2 Treg 10/23|4 Nature Review Immunology Immunotherapy combination approaches:mechanisms,biomarkers and clinical observations Lisa H.Butterfield IL2,IL4,IL7,IL 9,IL15 IL21 IL-2 T T CD4+T IL-2 IL-2 1 IL-2 T NK 2 IL-2 CD4+CD25+T Treg Treg IL15 IL2 IL 15 11/23|5 Nature Reviews Harnessing cytokines and chemokines for cancer therapy David J.Propper PD1/PDL1 CD47/SIRP IL-2 IL-15 IL-2/IL-15 6 12/23|2.IL2 IL-2 IL-2R 3 IL-2R IL-2R IL-2 IL-2R CD25 IL-2 Kd=10nmol/L IL-2 IL-2R IL-2R IL-2R IL-2R IL-2R IL2R/IL-2 IL-2R IL-2R IL-2R/IL-2 IL-2R/IL-2R CD122 IL-2R CD132 Kd=1nmol/L IL-2/Kd=10pmol/L JAK/STAT5 PI3K/Akt/mTOR MAPK 7 IL-2R International Journal of Cancer CD25:A potential tumor therapeutic target Yujia Peng Nature Biology and regulation of IL-2:from molecular mechanisms to human therapy Rosanne Spolski Nature Engineering IL-2 for immunotherapy of autoimmunity and cancer Rosmely Hernandez 13/23|2.1 IL-2 IL-2 1 IL-2 IL-2 IL-2 CD-25 IL-2 2 CD25 RIC CD25 IT ADC CD25/IL-2 IL-2 15KDa 1+IL-2 8 IL2 IL-2 MOA/IL-2 Proleukin IL-2R/T Novartis,Clinigen 1991 FDA IL-2 NKTR-214 CD122(IL-2R)IL-2R PEG Teff BMS Ph3(PD1)THOR-707 CD122(IL-2R)IL-2R PEG Teff Sanofi Ph2(PD1)SHR-1916 CD122(IL-2R)IL-2R PEG Teff Ph1-IL2 hu14.18-IL2(EMD273063)GD2/IL2/Teff EMD Serono Ph2 L19-IL2 ED-B/IL2/Philogen S.p.A.Ph2 CTLA4 RO6874281 FAP IL-2Ry Teff Roche Ph2 IL-2R(CD25)IgG1 T Novartis 1998 IL-2R(CD25)IgG1 T AbbVie and Biogen 2018()14/23|IL-2R(CD25)IgG1 T ElsaLys Biotech RG6292 IL-2R(CD25)IgG1 Fc Treg Roche(Tusk Therapeutics)Ph1,PD-L1 CD25 RIC 90Y-IL-2R(CD25)RIC CD25+Ph1 90Y-IL-2R(CD25)RIC CD26+NIH Ph2(-CD25 IT LMB-2 IL-2R(CD25)IT/CD25+NIH Ph2 Ontak IL-2R(CD25)T IT/CD25+Eisai Inc 1999 FDA ADC ADCT-301 IL-2R(CD25)ADC PBD CD25+ADC Therapeutics Ph2 International Journal of Cancer CD25:A potential tumor therapeutic target Yujia Peng IL-2 2018 BMS 36.5 Nektar IL-2 2019 25 Synthrox IL-2 THOR-707 2020-2023 IL2 IL-2 IL-2R 9 IL2 2023-12-06 Coya Therapeutics Dr.Reddys Laboratories Coya 302()IL-2/CTLA4-Fc 733.2 7.5 2023-02-22 Cue Biopharma Ono Pharmaceutical CUE-401()IL-2/TGF-Fc 220.0 0.0 2023-01-01 Clinigen Iovance Biotherapeutics()IL-2 223.1 178.4 2022-09-29 Almirall SIM0278()IL-2-Fc 507.0 15.0 2021-02-17 Nektar Therapeutics SFJ Pharmaceuticals Bempegaldesleukin(III)IL-2R/IL-2R;150.0 0.0 15/23|IL-2 2021-02-01 Coherus BioSciences LTC002 IL-2 290.0 35.0 2020-12-07 KaliVir Immunotherapeutics Astellas Pharma VET2-L2()307.0-2020-08-29 LTC002()IL-2 135.1 3.0 2020-01-01 Ambrx ARX102()IL-2-2019-12-09 Synthorx THOR707 IL-2 2500-2019-02-13 Novartis Clinigen()IL-2 210.0 120.0 2018-07-01 Sutro Biopharma Merck&Co.other two research programs;MK-1484()-1690.0 60.0 2018-02-14 Nektar Therapeutics Bristol-Myers Squibb Bempegaldesleukin(I/II)IL-2R/IL-2R 3650.0 1000.0 2017-07-24 Nektar Therapeutics Eli Lilly Rezpegaldesleukin(I)IL-2R 400.0 150.0 2007-04-11 Transgene Roche tipapkinogen sovacivec(II)298.9 17.8 2006-09-08 Ligand Pharmaceuticals Eisai()anti-IL-2R-2.2 PD1/IL-2R bias IBI363 CD25+CD8+T IBI363 Fc IL-2 PD-1 IL-2R-bias CD25+CD8+T PD-1 TST IL-2 IL-2-CD25 IFN TNF-GZMB CD25 IL-2n Treg CD25+TST IL-2n TME CD25-TST 16/23|IL-2n IL-2wt/Treg IL-2 10 IBI363 Nature Cancer IL-2R-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+T cells Weiwei Wu IBI363 IBI363 vs K ORR 32%vs 14.5%IBI363 vs K ORR 30.8%vs 12%DCR 76.9%vs 70%ORR 35.1%vs 14.3%mPFS 5.5m vs 2.1m 11 IBI363 vs K IBI363 PD-1/IL-2-bias PD1 NCT05460767 KEYNOTE-030 NCT03475004 KEYNOTE-032 Ph1 Ph1 Ph1 a/b Ph3 Ph2 Ph1 100g/kg QW 2mg/kg Q3W IBI363 100 g/kg QW 3mg/kg Q3W IBI363 0.3mg/kg IBI363 2mg/kg Q3W 2 mg/kg 10 mg/kg 200 mg Q3W 67 68 70 947 50 42 17/23|III/IV/89.6%61.2%2 25.4%70.1%83.8%MSS/pMMR MMR 76.5%3 61.8%77%2 1 BRAF/MEK 2 MSS BRAF mCRC/67%2 41%EFGR TKI 45%EGFR-5.3m 5.7m-7.9m 2024 1 11 2023 12 22-2017 9 19 52 25 1mg/kg Q2W IBI363 1mg/kg 37 0.3mg/kg IBI363 36 PD-(L)1,1 TCE-50 42 2 mg/kg n=14;10 mg/kg n=13;200 mg n=15 mPFS-5.5m 5.9m 2.1m mOS-9.3m ORR 32%15%30.8%PD-L1 CPS 1 13 35.1%100%3mg/kg 27.1%70 14.5%22.1%1 12%14.3%CR-1.9%12-DCR 80%76.9%PD-L1 CPS 1 13 75.7%100%3mg/kg 72.9%70-70%-mDoR-16 23.9%3 TEAE 8 11.9%3 TEAE 34.3%29.9%25.4%22 32.4%3 TEAE 4 5.9%3 TEAE 35.3%32.4%22.1%20.6%-181 19.1%AE 8.0%/7.3%6.4%;29 3.1%1 3/4 AE 56%8%3 4;12%12%29 69%AE 3-4 4/42 10%;5 12%AE ASCO 2024 ESMO 2024 Journal of Immunotherapy Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States:An Expanded Access Program Gangadhar Clin Cancer Res A phase II study of potentiation of pembrolizumab with binimetinib and bevacizumab in refractory microsatellite stable colorectal cancer Robert W Lentz The Oncologist KEYNOTE 032:A Randomized Phase I Study of Pembrolizumab in Chinese Patients with Advanced Non Small Cell Lung Cancer Yuxiang Ma 18/23|3.IL15 IL15 2024 4 ImmunityBio IL15/IL15R-Fc N-803 FDA(CIS)BCG(NMIBC)3.1 IL15 IL-15 CD8 T IL-15 IL-15 IL-15R IL-2R NK NKT CD8 T IFN-IFN-IL-15 12 IL-15 Cytokine and Growth Factor Reviews Immunobiology of the IL-15/IL-15R complex as an antitumor and antiviral agent Yin Guo IL-15 1 IL-15 IL-15 IL-15 19/23|2 IL-15 RLI IL-15 IL-15R Sushi IL-15 IL-15/IL-15R-IgG1-Fc ImmunityBio N-803 IL-15N72D/IL-15R-IgG1-Fc IL-15 IL-15N72D IL-15R Sushi IgG1 Fc 13 IL-15 Cytokine and Growth Factor Reviews Immunobiology of the IL-15/IL-15R complex as an antitumor and antiviral agent Yin Guo N-803 BCG Ta/T1 NMIBC N-803+BCG vs K mDFS 19.3m vs 7.7m 12mDFS 55.4%vs 43.5%14 N-803 ImmunityBio N-803 IL-15 PD1 QUILT-3.032 KEYNOTE-057 Ph3 Ph2 N-803 400ug/+BCG 50ug/N-803 400ug/+BCG 50ug/N-803 400ug/200mg Q3W 82 A 72 B 10 C 132 B 20/23|BCG CIS Ta/T1 BCG Ta/T1 NMIBC BCG CIS Ta/T1 BCG NMIBC Ta/T1 80%12 BCG 43%TURBT 3 23%54%12 BCG 49%TURBT 3 14%70%12 BCG 40%TURBT 3 10%10 28%PD-L1 CPS 10 23.9m 20.7m 7.9m-mDFS-19.3m-7.7m 12m DFS-55.4%-43.5%54.1%PDL1 CPS 10 CR 71%-20%-mDoR 26.6m-3 TEAE 2%2%1%5 TEAE 3 3 TEAE 1 1%10 7 70%TEAE TEAE 1 2 1 3 73%TEAE 14%3 AE 2%2%11%NEJM IL-15 Superagonist NAI in BCG-Unresponsive Non Muscle-Invasive Bladder Cancer Karim Chamie The Lancet Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG(KEYNOTE-057):a single-arm,multicentre,phase 2 trial 3.2 IL15 IL-15 IL-15 IL-15 IL-15 IL 15(A)(M)(C)Sushi(S)Sushi IL15 Sushi IL15 IL 15 IL-15()21/23|15 IL15 Askgene 16 ASKG315 ASKG915 ASKG315 ASKG915 PBMC 10 x/Y Y Y Y PK-T1/2 10d 5d AUC 20 x/NK 12x/NK 3/Askgene 22/23|4.PD1/IL2 PD1/IL15 PD1/IL2 PD1/IL15 BD PD1/PDL1 K 2023 250+PD1/IL2 PD1/IL15 PD1/IL2 PD1/IL15 IL-2na PD1/IL2 R-bias IL-15 N-803 FDA NMIBC PD1/IL15 5.23/23|6 12 6 12 A 300 50 500 10%5%10%-5%5%-5%/208 A 4 188 8 8 16 4068 1 13