医药百页深度：双抗潮涌波澜壮阔.pdf

1 / 90 | 2021 6 6 陈梦洁 S0300520100001 010-64814022 12 ASCO 2021-05-24 2021-05-28 12 2021-05-31 bsAb Bispecific Antibody DNA Fc IgG Fc IgG Fc Fc IgG HL Fc FcRn ADCC CDC ADCP Fc IgG Fc Fc IgG Fc IgG KiH CrossMab YBODY FIT-ig IgG BiTE Fc Affimed TandAbs Nanobody / 1 / T TCR T T CD3 -2% 10% 22% 33% 45% 20-06 20-09 20-12 21-03 21-06 沪深300 医药生物 2 / 90 CD3 2 3 Trion Pharma CD3 EpCAM Catumaxomab CD3 CD19 Blinatumomab FIX FX Emicizumab EGFR c-Met Rybrevant License in AK104 KN046 6 3 / 90 . 8 . 9 Fc IgG . 10 Fc IgG . 11 . 12 Fc IgG . 12 Fc IgG . 19 . 23 / . 24 . 28 . 32 . 34 Removab . 35 Blincyto . 38 Hemlibra . 40 Rybrevant EGFR Exon20Ins NSCLC . 42 . 44 . 46 . 51 . 62 . 70 . 72 . 82 . 82 . 84 . 85 . 85 . 86 . 87 . 87 . 88 4 / 90 1 . 8 2 . 9 3 Fc IgG Fc IgG . 9 4 FcRn . 10 5 Fc IgG . 11 6 Fc IgG . 11 7 . 12 8 . 13 9 Fc IgG . 13 10 KiH . 14 11 KiH CrossMab . 15 12 YBODY . 15 13 DVD-ig . 16 14 FIT-ig . 17 15 HBICE . 17 16 CRIB . 18 17 AK104 . 18 18 Fc IgG . 19 19 Blincyto . 19 20 BiTE . 20 21 BiTE HLE BiTE . 20 22 DART . 21 23 TandAbs . 21 24 TandAbs . 22 25 Nanobody . 22 26 Nanobody . 23 27 T . 23 28 . 24 29 MHC- TCR . 25 30 / T . 25 31 Blincyto . 26 32 NK ADCC . 26 33 AFM13 . 27 34 AFM13 . 27 35 . 28 36 . 28 37 / . 29 5 / 90 38 AK104 . 29 39 AK104 PD-1 CTLA-4 . 30 40 GEN-1046 . 31 41 ES101 . 31 42 RTK . 32 43 KN026 . 33 44 VEGF . 34 45 . 35 46 . 35 47 . 35 48 . 36 49 2009-2013 . 37 50 Removab . 37 51 . 38 52 . 38 53 BiTE . 38 54 2014-2020 Blincyto . 39 55 . 40 56 Hemlibra . 40 57 Hemlibra . 41 58 HAVEN2 . 42 59 EGFR . 42 60 HGF/ Met . 43 61 Rybrevant . 43 62 . 45 63 . 46 64 AK104 . 47 65 PD-1 CTLA-4 FDA . 47 66 AK104 . 48 67 AK104 . 48 68 AK104 . 49 69 AK104 G/GEJ . 50 70 AK112 . 50 71 AK112 + . 51 72 . 51 73 CRIB . 52 74 KN046 . 53 75 KN046 . 53 76 KN046-201 . 55 6 / 90 77 KN046-201 . 55 78 KN046-201 PFS . 55 79 KN046-201 OS . 55 80 KN046 PD-1 . 55 81 KN046-201 . 56 82 KN046-203 . 56 83 KN046 . 57 84 KN046 AK104 . 58 85 KN026 . 58 86 KN026 . 59 87 KN026 . 59 88 KN026-201 . 60 89 KN026-201 . 60 90 KN026-201 . 61 91 KN026-201 . 61 92 KN026+KN046 . 62 93 KN046-IST-02 . 62 94 KN046-IST-02 . 62 95 . 62 96 PD-1/PD-L1 . 63 97 IBI-318 . 63 98 AMD . 64 99 IBI-302 . 66 100 PENTAMBODY . 66 101 4-1BB PD-(L)1 . 67 102 CD47-SIRP . 68 103 CD47 . 69 104 FGL1-LAG3 . 70 105 TGF- . 71 106 IBI-302 . 72 107 . 72 108 BCMA . 73 109 BiTE HLE BiTE . 73 110 BCMA CD3 . 74 111 2015 . 75 112 . 76 113 AMG160 . 76 114 ZW25 . 78 115 ZW25 . 78 7 / 90 116 Azymetric . 78 117 ZW25 . 79 118 ZW25 . 79 119 ZW49 . 80 120 ZymeLink . 81 121 JS201 . 82 122 M701 . 82 123 YBODY . 83 124 ITab . 84 125 ExMab . 85 126 PM8001 . 86 127 EMB-01 . 87 128 Multiclonics . 87 129 MCLA-129 ADCC ADCP . 88 8 / 90 bsAb Bispecific Antibody T CD3 T TCR T T Nature Review Drug Discovery 2019 3 CD3 1 lookfordiagnosis 1 2 3 100-1000 1/2000 9 / 90 2 BiTE 1 2 IgG 80KD scFv 55-60KD - 100-1000 ADCC CDC ADCC CDC PD-1 CTLA-4 EGFR/cMET EGFR EGFR cMET EGFR/cMET Fc DNA Fc 1 Fc IgG 2 Fc IgG Fc 3 Fc IgG Fc IgG Fc IgG Fc IgG KiH CrossMAB DVD-ig Orthogonal Fab IgG BiTE Nanobody DART Catumaxomab Blincyto CMC Fc ADCC CDC ADCP CMC Fc BioValley 10 / 90 Fc IgG Fc IgG HL Fc Fc IgG KiH CrossMab DVD-ig Orthogonal Fab IgG Fc IgG 1 Fc FcRn Fc Fc 2 Fc A/G 3 Fc IgG bsAb Fc ADCC CDC ADCP 4 FcRn Nature Reviews Drug Discovery 1 Fc 2 3 Fc T Fc 11 / 90 5 Fc IgG ThermoFisher Fc IgG Fc IgG Fc IgG bsAb BiTE Nanobody Fc IgG 1 2 3 Fc 6 Fc IgG ThermoFisher Fc 1 2 half life PEG Fc PEG PEG Fc pH FcRn 12 / 90 ABD XTEN CTP 7 Fc IgG 16 DNA DNA A T G C A C G T G C - 1 2 13 / 90 8 Fc IgG KiH CrossMab DVD-ig Orthogonal Fab IgG YBODY FIT-Ig CRIB 9 Fc IgG 技 术平台 公司 Triomab Trion Knob-in-Hole Roche Genentech CrossMab Roche Dutalys ART-IgG Roche Chugai DVD-Ig Abbvie Azymetric Zymeworks EFECT Zymeworks YBODY FIT-Ig CRIB Tetrabody WuxiBody DPL MabPair TEAC GNC HCAb HBICE 1 Knob-in-Hole KiH KiH CH3 CH3 366 T W Knob 366 T S 368 L A 407 Y V Hole Hole Knob 14 / 90 KiH CH3 Fc KiH Knob 90% KiH KiH 10 KiH GenScript 2 CrossMab / CrossMab KiH CrossMab Abs Fab VH-VL CH1-CL CrossMab CH1-CL CH1 CL CrossMab VH-VL VH VL CrossMab Fab CH1-VH CL-VL VH VH CL CL 15 / 90 11 KiH CrossMab 3 YBODY scFv YBODY Knob-in-hole / YBODY Fc N scFv YBODY scFv T CD3 CD3 T T 12 YBODY 16 / 90 4 DVD-Ig N VL VH DVD-Ig Dual Variable Domain-Ig IgG N VL VH 2 VH VH 2 VL VL 2 Fc DVD-ig 13 DVD-ig GenScript 5 FIT-Ig FIT-Ig Fabs-In-Tandem CEO DVD-Ig FIF-ig Fab N Fab Fab 250kDa 3 DVD-Ig FIT-Ig FIT-Ig 1.FIT-Ig 2.FIT-Ig 17 / 90 14 FIT-ig 6 HCAb HBICE HCAb nanobody IgG IgG Fc HCAb HCAb HBICE HCAb HBICE CD3 HBICE 15 HBICE 18 / 90 7 CRIB CRIB CRIB Fc CMC Fc BsAb CRIB CRIB 16 CRIB 8 Tetrabody Tetrabody CMC PD-1/CTLA-4 AK104 PD-1/VEGF AK112 Tetrabody ACE 17 AK104 19 / 90 Fc IgG Fc IgG Fc IgG Fc VH VL Fab Fc IgG 150kDa IgG 60kDa IgG FcRn Fc IgG 2 Fc IgG BiTE Nanobody MacroGenics DART 18 Fc IgG 技 术平台 公司 BiTE Micromet/ DART MacroGenics Bi-nanobody Ablynx/ TandAbs Affimed Probody CytomX 1 HLE BiTE Fc BiTE Bispecific T-cell Engager T Micromet 2012 Micromet BiTE Blincyto Blinatumomab BiTE 2020 12 19 Blincyto Bispecific Antibodies Design Therapy Perspectives 1 BiTE scFv T CD3 scFv scFv T T 20 / 90 2 55-60kDa 55kD half-life extended(HLE) BiTE BiTE HLE BiTE Fc BiTE Fc IgG Fc FcRn HLE BiTE AMG160 AMG757 20 BiTE 21 BiTE HLE BiTE 2 DART Fc DART Dual affinity re-targeting MacroGenics Linker VL VH VL VH scFv scFv VH VL 1 T 2 DART 3 BiTE DART T 56KD BiTE MacroGenics DART Fc 21 / 90 22 DART MacroGenics 3 TandAbs TandAbs Affimed scFv TandAbs N C VL1-VH2-VL2-VH1 23 TandAbs Affimed Therapeutics 1 TandAbs 110kDa IgG 23 ; 2 TandAbs 3 TandAbs T /NK 22 / 90 24 TandAbs Affimed Therapeutics 4 Bi-Nanobody Nanobody VHH CH2 CH3 Ablynx 2018 VHH Nanobody Nanobody 25 Nanobody Ablynx Nanobody 1 Nanobody 12-15kDa 2 scFv Nanobody 3 Nanobody VH Nanobody Ablynx Nanobody FcRn 3 23 / 90 26 Nanobody Ablynx / T / T T -MHC T TCR T T APC Costimulation TCR T 27 T Cancer Discovery 24 / 90 / TIL TIL 4 0 TIL / Altered-excluded altered-Immunosuppressed CD3+ CD8+ 28 Nature / Tumor Immune Escape T CD8+T TCR MHC- - MHC TCR MHC 25 / 90 29 MHC- TCR Nature Reviews T TCR T T T 30 / T lookfordiagnosis 26 / 90 T CD3 CD3 CD3 CD3 T T Nature Review Drug Discovery 2019 3 CD3 Blincyto CD19 CD3 Blincyto T TCR CD3 B CD19 T CD19 ALL ALL 31 Blincyto Bispecific Antibodies Design Therapy Perspectives CD3 Removab CD3 EpCAM 2010-2012 332 443 454 2017 Removab Removab Removab T T Fc Blincyto BiTE FC IgG scFv T NK Fc NK FcR Fab ADCC 32 NK ADCC 27 / 90 Immunol AFM13 CD16A CD30 100KD T CD16A NK Fc IgG1 ADCC CD16A 158V 158F 158F IgG1-Fc ADCC 33 AFM13 Affimed AFM13 NK CD30 ADCC ADCP 2021AACR AFM13 / CD30 ORR 100% 4 CR PR 34 AFM13 Affimed 28 / 90 T APC Antigen Presenting Cell T T T 35 Cancer Discovery PD-1 CTLA-4 CTLA-4 PD- L 1 LAG-3 TIM-3 TIGIT VISTA OX40 CD28 CD27 GITR ICOS 36 29 / 90 Talks 1 PD-1 CTLA-4 PD-1 CTLA-4 TRAE CheckMate 067 PD-1 3-4 22% CTLA-4 3-4 28% 3-4 59% PD-1 CTLA-4 TIL Tumor Infiltrating lymphocyte TIL TRAE AK104 PD-1 CTLA-4 TIL TIL 37 / 38 AK104 30 / 90 PD-1 CTLA-4 CTLA-4 PD-1 TIL PD-1 CTLA-4 PD-1/CTLA-4 39 AK104 PD-1 CTLA-4 2 + CD27 CD40 OX40 GITR 4-1BB 4-1BB 4-1BB T 4-1BB T CTL NK 4-1BB 4-1BB BMS Urelumab BMS-663513 4-1BB GEN-1046 PD-L1/4-1BB 2019 6 BioNTech DuoBody PD-L1/4-1BB GEN-1046 / a PD-L1 PD-1/PD-L1 4-1BB 4-1BB 2020 SITC / a GEN-1046 31 / 90 40 GEN-1046 2020 SITC ES101 ES101 PD-L1 4-1BB ES101 PD-L1 T 4-1BB ES101 PD-L1 PD-1/PD-L1 ES101 T 4-1BB ES101 PD-L1 4-1BB 4-1BB T 4-1BB T ES101 PD-L1 PD-L1 4-1BB PD-L1 T 41 ES101 32 / 90 Receptor Tyrosine Kinase RTKs RTKs EGFR PDGFR VEGFR FGFR RTKs 42 RTK TKI TKI NCCN EGFR EGFR-TKI TKI 612 TKI T790M EGFR c-Met FGFR PI3K AKT 1 33 / 90 HER HER HER KN026 HER2 HER2 D2 D4 KN026 HER2 HER2 HER2 MBS301 HER2 D2 D4 ADCC 43 KN026 2 2mm VEGF IBI302 VEGF N VEGF VEGF AMD IBI302 C C3b C4b AMD 34 / 90 44 VEGF 3 TNF- IL-6 TGF- IL-10 IL-13 IL-4 KIH SAR156597 TNF- IL-17A DVD-IG ABT-122 2021 6 Trion Pharma CD3 EpCAM Catumaxomab CD3 CD19 Blinatumomab FIX FX Emicizumab EGFR cMet Rybrevant CD3 EpCAM M701 YBODY EpCAM A-337 ITab TM CD3 CD19 K193 Fabite 2019 / B A319 ITab TM TAA CD19 CD3 T EX102 ExMab 35 / 90 45 FDA EMA NMPA Removab CD3 EpCAM Trion Pharma - 2009 2017 - Blincyto CD3 CD19 2014 2015 2020.12 Hemlibra FIX FX 2017 2018 2018.12 A - Rybrevant EGFR c-Met 2021 - - 46 CD3 EpCAM / 2021-04-12 / 2020-07-17 M701 I 2018-08-14 A-337 2017-06 - CD3 CD19 K193 / B I 2019-11-18 A319 B 2018-11 - EX102 B - - B-193 - - Removab Catumaxomab Trion Pharma Removab T CD3 EpCAM Ascension GmbH 1998 Trion Pharma 47 36 / 90 Fc Trifunctional Antibodies EpCAM T CD3 Fc NK Fc T 48 Triomab Fc IgG Removab Trion Pharma Triomab CD3 IgG2b IgG2a CH/CH CL/CH Triomab IgG 1 / 2 / Protein A 3 4 2.13d 150ug / EpCAM 99.9% 23 6 TNF- IL-6 80% IL-6 60% TNF- / 83% 61% 57% 39% 26% ALP AST GGT / 15 37 / 90 EMA 2009 4 Removab EMA EpCAM 2009 Removab 2012 454 Removab 2014 2017 6 Removab 1 Removab Removab 2 Removab / 15% TRSAE 3 Removab 4 Removab 49 2009-2013 50 Removab EMA T / / 2023 2024 166 332 443 454 270 -60% -40% -20% 0% 20% 40% 60% 80% 100% 120% 0 100 200 300 400 500 2009 2010 2011 2012 2013 38 / 90 51 CTR20210616 Catumaxomab 2021-04-12 CTR20201246 Catumaxomab 2020-07-17 Blincyto Blincyto Blinatumomab CD19 CD3 T Blincyto B CD19 T CD3 CD19 B CD3+T Blincyto T 55KDa 52 Blincyto T BiTE BiTE scFv Fc Fc FcRN Blincyto 2 53 BiTE 39 / 90 FDA 2014 FDA B ALL 2018 Blincyto MRD B EMA Blincyto CD19 B ALL MRD 0.1% CD19 B ALL CD19 B ALL NMPA Blincyto 2020 10 31 Blincyto 2020 12 NMPA Blincyto B ALL Blincyto 2020 3.79 21.47% Blincyto Blincyto 17.8 54 2014-2020 Blincyto 3 77 115 175 230 312 379 0% 10% 20% 30% 40% 50% 60% 0 50 100 150 200 250 300 350 400 2014 2015 2016 2017 2018 2019 2020 40 / 90 Blincyto Blincyto TOWER Blincyto 1 TOWER Blincyto / B-ALL OS 7.7 VS4 12 34%VS 16% DOR 7.3 VS4.6 R/R B-ALL 67 Blincyto CR 47.8% OS 9.6 2 Blincyto FDA Blincyto Blincyto Hemlibra A B A 80%85% A A 15%-25% A 55 /A /B Hemlibra IgG4 DNA CHO Hemlibra FIXa FX A F F A 56 Hemlibra 41 / 90 FDA 2017 11 FDA A 2018 4 A Hemlibra A 48.4 44.8 / NMPA 2018 12 4 Hemlibra NMPA A Hemlibra 2021 3 Hemlibra A 2020 Hemlibra 21.9 TOP100 A Hemlibra Hemlibra 8100 /30mg 2020 2020 57 Hemlibra HAVEN2 88 n=68 n=10 n=10 ABR Hemlibra 58 0.3 77% 3 Hemlibra 21.3 19.9 0.2 2.2 90.0% 60.0% Haven2 18 n=15 n=3 19.9 Hemlibra 3 224 1380 2190 0 500 1,000 1,500 2,000 2,500 2017 2018 2019 2020 42 / 90 99% 0.2 13 Hemlibra Hemlibra 58 HAVEN2 Rybrevant EGFR Exon20Ins NSCLC 2021 5 21 FDA EGFR/c-Met Rybrevant JNJ-372 EGFR 20 NSCLC Rybrevant EGFR 20 NSCLC cMet c-Mesenchymal-epithelial transition factor HGF Hepatocyte Growth Factor HGF/c-Met p53 c-Met c-Met 59 EGFR ASCO 43 / 90 cMet EGFR TKI c-Met c-Met EGFR TKI EGFR TKI C797S c-Met 2018 ESMO c-Met EGFR-TKI c-Met EGFR 60 HGF/ Met Merus Rybrevant Amivantamab JNJ-372 IgG1 FAB EGFR cMet Rybrevant Rybrevant EGFR c-Met EGFR c-Met Rybrevant EGFR c-Met Fc ADCC 61 Rybrevant 44 / 90 2019ASCO 1 Amivantamab EGFR Exon20ins NSCLC 2020 ASCO JNJ-372 EGFR 20 80kg 1050 mg 80kg 1400 mg 39 ORR 36% CBR 67% 10 PFS 8.3 29 ORR 41% CBR 72% PFS 8.6 3 AE 6% 3% 2 Amivantamab Lazertinib NSCLC 2021 ASCO Amivantamab 19 NSCLC 45 ORR 36% 16/45 CR 2% 1/45 ,PR 33% 15/45 8.2 mPFS 4.9 60 45 / 90 62 6 Blincyto CD3 CD19 ZW25 HER2 HER2 AMG701 CD3 BCMA AMG160 CD3 PSMA AMG199 CD3 MUC17 ZW49 HER2 HER2 ADC 6 IBI-302 C3 VEGF IBI-318 PD-1 PD-L1 IBI-315 PD-1 HER2 IBI-319 PD-1 4-1BB IBI-322 PD-L1 CD47 IBI-323 PD-L1 LAG-3 2 AK104 PD-1 CTLA4 AK112 PD-1 VEGF 2 KN046 PD-L1 CTLA4 KN026 HER2 HER2 5 SI-B001 EGFR HER3 GNC-039 PD-L1 CD3 4-1BB EGFR GNC-035 PD-L1 CD3 4-1BB ROR1 GNC-038 PD-L1 CD3 4-1BB CD19 SI-B003 PD-(L)1 CTLA-4 3 EMB-01 EGFR cMET EMB-02 PD-1 LAG-3 EMB-06 CD3 BCMA 2 A-337 CD3 EPCAM A-319 CD3 CD19 2 M802 CD3 HER2 M701 CD3 EPCAM 2 ES101 PD-L1 4-1BB ES104 VEGF DLL4 2 IMM0306 CD47 CD20 IMM2510 PD-L1 VEGF 2 PM8001 PD-L1 TGF- PM8002 PD-L1 VEGF 2 REGN1979 CD3 CD20 MGD013 PD-1 LAG-3 1 SHR-1701 PD-L1 TGF- 1 CD3-MUC1 CD3 MUC1 1 GB261 CD3 CD20 1 K193 CD3 CD19 1 CD3 EPCAM 46 / 90 1 HB0025 PD-L1 VEGF 1 MBS301 HER2 HER2 1 QL1706 PD-1 CTLA-4 1 TQB2858 PD-L1 TGF 1 JS201 PD-1 TGF 1 Q-1802 PD-L1 Claudin 18.2 1 MCLA-129 EGFR cMET 1 HX009 PD-1 CD47 1 SG12473 PD-L1 CD47 1 6MW3211 PD-L1 CD47 1 BJ-005 PD-L1 TGF- 2 AK104 PD-1 CTLA4 AK112 PD-1 VEGF 63 Tetrabody Tetrabody CMC PD-1/CTLA-4 AK104 PD-1/VEGF AK112 Tetrabody ACE 47 / 90 1 AK104 AK104 Tetrabody PD-1 CTLA-4 TIL 64 AK104 PD-1 CTLA-4 T T PD-1 CTLA-4 PD-1 CTLA-4 PD-1 CTLA-4 PD-1 CTLA-4 PD-1 CTLA-4 PD-1 CTLA-4 CTLA-4 PD-1 ORR FDA RCC 2018 4 MSI-H dMMR CRC 2018 7 65 PD-1 CTLA-4 FDA 2015 10 O +Y 2018 4 O +Y RCC 2018 7 O +Y 12 MSI-H dMMR CRC 2020 3 O +Y HCC 2020 5 O +Y PD-L1 EGFR ALK PD-1 CTLA-4 TRAE CheckMate 067 PD-1 48 / 90 3-4 22% CTLA-4 3-4 28% 3-4 59% AK104 PD-1 CTLA-4 TIL Tumor Infiltrating Lymphocyte AK104 PD-1 CTLA-4 TIL TIL PD-1 CTLA-4 CTLA-4 PD-1 TIL PD-1 CTLA-4 PD-1/CTLA-4 66 AK104 AK104 10 AK104 2021 4 28 AK104 CDE 3 AK104 / 3 67 AK104 49 / 90 1 2020 11 AK104 2020 31 2020 AK104 NDA AK104 ORR DCR 47.6% 66.7% PD-1 PD-1 CTLA-4 AK104 (TRAE) 12.9% PD-1 PD-L1 68 AK104 N ORR DCR AK104 31 47.6% 66.7% Agenus Balstilimab+Zalifrelimab PD-1+CTLA-4 143 21.6% - 160 14.0% - MSD 77 14.3% 31.2% 15 - 20% BMS O +Y (1mg/kg) 26 23.1% 53.8% O +Y (3mg/kg) 22 36.4% 72.7% 2020 Annual Results Presentation 2 AACR 2020 PD-1/CTLA-4 AK104 G/GEJ Ib/ G/GEJ 36 AK104 4 6 10mg/kg mXELOX 85mg/m 2 1000mg/m 2 2020 1 17 20 AK104 mXELOX AK104 4mg/kg 6mg/kg 17 3 15 ORR 60% 9/15 DCR 93.3% 7 50 / 90 1+ 168+ 1 40% PD-L1 AK104 AK104 TRAE 45% 3 TRAE 20% 4/20 4 TRAE TRAE TRAEs 15% 15% 15% 69 AK104 G/GEJ ORR DCR PFS 6 PFS AK104+mXELOX 4.9 66.2% 94.4% - 67.1% AK104+mXELOX 4mg/kg 11.4 68.8% 93.8% 9.6 76.5% 15.4 46.7% 80% 6.1 - MSD + 22.6 48.6% - 6.9 53% KEYNOTE-062 - 37.2% - 6.4 2020 Annual Results Presentation 2 AK112 AK112 PD-1/VEGF Tetrabody PD-1 VEGF VEGF PD-1 AK112 PD-1 VEGF PD-(L)1 VEGF FDA Tecentriq PD-L1 Tecentriq PD-1 VEGF PD-1/PD-L1 VEGF AK112 PD-1 VEGF AK112 PD-1 VEGF PD-1/PD-L1 VEGF-A , T T 2019 AK112 2019 6 AK112 FDA 2020 8 AK112 NMPA b 70 AK112 /EGFR-TKI 2021 - b 2021 - 51 / 90 2021 - 2021 - a/ b 2019 10 - / a AK117 - 2020 1 AK112 PK PD a AK112 MTD RP2D b AK112 MTD RP2D AE DLT Ia 2020 AK112 a PD-1 PD-1 11 4 ORR 36% 7 DCR 64% 2021 3 19 41 6 0.3mg/kg n=1 1mg/kg n=3 3mg/kg n=3 10mg/kg n=13 20mg/kg Q2W n=18 30mg/kg Q2W n=3 41 TRAE 63.4% 3 TRAE 19.5% + AK112 71 AK112 + AK112 N=29 Immotion151 1200mg+ 15mg/kg Q3W TRAE 16(55.2%) 91% Grade 3 TRAE 3(10.3%) 40% Drug-related SAE 1(3.4%) Not reported TRAEs leading to discontinuation 2(6.9%) 5% 2020 / 16 15 1 2021 2-3 IND KN035 72 52 / 90 2020 1 sdAb KN046 PD-L1 CTLA-4 sdAb 2 CRIB CRIB Fc CMC Fc BsAb CRIB CRIB 73 CRIB 53 / 90 1 KN046 KN046 BsAb sdAb Fc sdAb PD-L1 CTLA-4 KN046 10 20 PD-1 KN046 2022 74 KN046 1 KN046 CTLA-4 PD-L1 PD-L1 Treg Nanobody 2 Fc Fc Fc KN046 Fc T KN046 3 CTLA-4 CTLA-4 B7 CTLA-4 KN046 CTLA-4 sdAb CDR CTLA-4/B7 75 KN046 54 / 90 KN046 KN046 / KN046 1 EGFR ALK KN046-201 TKI NSCLC EGFR ALK 23 22 KN046 3.0mg/kg Q2W 7 PR PR SD DCR 85.7% ORR 28.6% KN046-201 22 20 3.0mg/kg Q2W 22 16 72.7% TEAE 9.1% 3 TEAE 18.2% SAE 31.8% irAE 55 / 90 76 KN046-201 77 KN046-201 2021WCLC KN046 NSCL