Background
CD22 structure, function, and expression
CD22 ADC structures and preclinical results
ADC/recombinant immunotoxin | Anti-CD22 antibody | Cytotoxic payload | Linker | Disease |
---|---|---|---|---|
BL22 | RFB4 dsFv | Pseudomonas exotoxin A (PE38) | mc-VC-PABC (enzyme cleavable) | R/R HCL |
Moxetumomab pasudotox/HA22 | RFB4 dsFv (SSY-THW) | Pseudomonas exotoxin A (PE38) | mc-VC-PABC (enzyme cleavable) | R/R B-cell HCL |
Pinatuzumab vedotin | Hu10F4 antibody | Monomethyl auristatin E | mc-VC-PABC (enzyme cleavable) | R/R B-cell NHL |
Anti-CD22-NMS249 | Hu10F4 antibody | PNU-159682 | mc-VC-PABC (enzyme cleavable) | R/R B-cell NHL |
Anti-CD22-(LC:K149C)-SN36248 | Hu10F4 antibody | SN36248 × 2 | maleimide linker (uncleavable) | B-cell NHL |
Inotuzumab ozogamicin | G544 antibody | Calicheamicin (Calich-DMH) | hydrazone (acid-labile linker) | R/R B-ALL |
Efficacy and safety of CD22 ADCs
Clinical trial information | Agent | Institution | Disease and patients (single agent cohort) | Prior CD19-targeted therapy | ORR(≥ CR, best response) | Veno-occlusive disease | Median PFS | Median OS |
---|---|---|---|---|---|---|---|---|
Phase 1 NCT00717925 [52] | Inotuzumab ozogamicin | Nagoya Daini Red Cross Hospital | R/R FL 13 pts | Rituximab 100% | 85% (54%) | - | - | - |
Phase 1 [53] | Inotuzumab ozogamicin | Multicenter | R/R B-cell NHL 79 pts | - | FL (MTD): 68% (-) DLBCL (MTD): 15% (-) | 1.30% | FL: 317 days DLBCL: 49 days | FL: not reached DLBCL: 193 days |
Phase 2 NCT01134575 [54] | Inotuzumab ozogamicin | MD Anderson Cancer Center | R/R B-ALL 90 pts | - | 58% (58%) | 6.7% | mDOR 7 mos | 6.2 mos |
Phase 3, 2-arm NCT01564784 (INO-VATE) | Inotuzumab ozogamicin | Multicenter | R/R B-ALL 164 pts | - | - (74%) | 14% | 5 mos | 7.7 mos |
Phase 2 NCT00868608 [57] | Inotuzumab ozogamicin | Multicenter | Refractory indolent B-NHL 81 pts | - | 67% (31%) | - | 12.7 mos | not reached |
Phase 1/2 NCT01363297 [58] | Inotuzumab ozogamicin | Multicenter | R/R B-ALL 72 pts | - | -(68%) | 5.6% | 3.9 mos | 7.4 mos |
Phase 1 EUDRA-CT 2016–000227-71 [59] | Inotuzumab ozogamicin | Multicenter | R/R B-ALL 25 pediatric pts | Blinatumomab 24% CAR-T 4% | 80% (60%) | 8% | - | DL1: 7.2 mos DL2: not reached |
Phase 2 EUDRA-CT 2016–000227-71 [60] | Inotuzumab ozogamicin | Multicenter | R/R B-ALL 28 pediatric pts | Blinatumomab 25% | 82% (82%) in 27 evaluable pts | 25% | 1-year EFS 36.7% | 1-year OS 55.1% |
Phase 2 NCT02981628 [61] | Inotuzumab ozogamicin | Multicenter | R/R B-ALL 48 pts | CAR-T 23% Blinatumomab 29% | 65% (58%) | 13% | 2-year EFS 28.6% | 2-year OS 36% |
Phase 1 NCT01209130 [62] | Pinatuzumab vedotin | Multicenter | R/R DLBCL 25 pts indolent B-cell lymphoma 38 pts CLL 10 pts | - | DLBCL: 39% (18%) indolent B-cell lymphoma: 32% (12%) CLL: 0% (0%) | - | indolent B-cell lymphoma: 7.6 mos DLBCL (PR2D): 4 mos | - |
Improving the clinical efficacy of CD22 ADCs
CD22 CAR-T cell structures and preclinical results
Efficacy and safety of CD22 CAR-T cell therapy
Clinical trial information | Institution | Transduction/costimulatory domain/scFv (CAR-T product or manufacture procedure) | Disease and patients | Prior CD19 CAR-T | CD19 negative or dim | Dosage | Pharmacokinetics | ORR(≥ CR, best response) | Prognosis | CRS at any grade (grade ≥ 3), evaluation criteria | Neurotoxicity at any grade (grade ≥ 3), evaluation criteria |
---|---|---|---|---|---|---|---|---|---|---|---|
Phase 1 NCT02315612 [20] | NCI | Lentivirus/4-1BB/m971 | R/R B-ALL 21 pts | 71.4% | 47.6% | 0.3 × 106 cells/kg 1 × 106 cells/kg 3 × 106 cells/kg | Peak on D14, persist up to 18 mos | 57% (57%) | - | 76% (0%) Lee criteria | 37.5% (0%) in first 16 patients |
Phase 1 NCT02315612 [24] | NCI | Lentivirus/4-1BB/m971 (CD4/CD8 TCS) | R/R B-ALL 57 pts R/R DLBCL 1 pt | 62% | 56.9% | 0.3 × 106 cells/kg 1 × 106 cells/kg 3 × 106 cells/kg | Peak on D14—D21, higher in those at CD4/CD8 TCS cohort | 71.9% (70.2%) in evaluable 57 pts | mRFS (CR) 6.0 mos mOS (CR) 13.4 mos | 86.2% (8.6%) Lee criteria | 32.8% (1.7%) ASTCT criteria |
Phase 1 ChiCTR-OIC-17013523 [21] | Beijing Boren Hospital | Lentivirus/4-1BB/- (YK-CD22BB-002) | R/R B-ALL 34 pts | 91% | 41.2% | 0.2 ~ 34.7 × 105 cells/kg | Peak on D12—D15 median persistence time was 28 days by FCM | 81.3% (78.1%) in 32 evaluable pts | - | 91.2% (2.9%) Lee criteria | 17.6% (0%) CTCAE criteria |
Phase 1 ChiCTR2000028793 [31] | Beijing Boren Hospital | Lentivirus/4-1BB/- (CD22-CARFH80) | R/R B-ALL 8 pediatric pts | 100% | 12.5% | 0.68 ~ 9.4 × 106 cells/kg | Peak on D11- D15 | 87.5% (75%) | - | 87.5% (12.5%) ASTCT criteria | ICANS 25% (12.5%) ASTCT criteria |
Two pilot studies NCT02650414 and NCT02588456 [81] | UPenn/Children’s Hospital of Philadelphia | Lentivirus/4-1BB/m971 (CART22) | R/R B-ALL 3 adult pts / 5 pediatric pts | 25% | 75% | 39.6 ~ 500 × 106 cells/pt | 2 CR pts showed significant CAR-T expansion within D20 | 50% (50%) | - | 75% (12.5%) Penn criteria | - |
Phase 1 PLAT-07(NCT04571138) [25] | Seattle Children's Hospital | - /4-1BB/m971 (SCRI-CAR22v2) | R/R B-ALL 3 pts | 100% | 66.7% | 2 × 105 cells/kg | - | 100% (100%) | - | - | - |
New Treatment Measure Clinical Study ChiCTR1800019298 [26] | Tianjin First Central Hospital | -/4-1BB/- | R/R B-ALL 6 pts R/R DLBCL 7 pts | 100% | 33.3% (B-ALL) | DLBCL: 2.11 ± 0.24 × 106 cells/kg B-ALL: 2.07 ± 0.42 × 106 cells/kg | Peak on D14 | DLBCL: 85.7% (57.1%) B-ALL: 33.3% (33.3%) | - | DLBCL: 42.9% (0%) B-ALL: 100% (16.7%) Lee criteria | ICANS 0% (0%) ASTCT criteria |
Phase 1 NCT04150497(BALLI-01) [27] | Cellectis S.A | Lentivirus/4-1BB/- (UCAR-T22, disruption of TRAC and CD52 genes using TALEN technology) | R/R B-ALL 3 pts | 33.3% | - | ~ 1 × 106 cells/kg | Peak on D9—D14 | 66.7% (33.3%) | - | 33.3% (0%) | 0% (0%) |
Phase 1 NCT04088890 [28] | Stanford University School of Medicine | Lentivirus/4-1BB/m971 (CD4/CD8 T selection) | R/R LBCL 3 pts | 100% | 66.7% | 1 × 106 cells/kg | Peak on D14, persist up to 3 mos by qPCR | 100% (100%) | - | 100% (0%) ASTCT criteria | ICANS 0% (0%) ASTCT criteria |
Phase 1 NCT04088890 (cohort expansion) [29] | Stanford University School of Medicine | Lentivirus/4-1BB/m971 | R/R LBCL 21 pts | 95% | - | 1 × 106 cells/kg 3 × 106 cells/kg | Peak on D14 | 85.7% (66.7%) | mPFS not reached mOS not reached | 100% (4.8%) ASTCT criteria | ICANS 19% (0%) ASTCT criteria |
Phase 1 NCT02650414 [30] | UPenn | Lentivirus/4-1BB/m971 (CART22-65 s) | R/R B-ALL 17 pts | 94.1% | 100.0% | 0.8 ~ 10 × 106 cells/kg (3—day fractionated dosing) | Peak on D20 | 76.5% (76.5%) | mRFS 5.3 mos mEFS 5.8 mos mOS 16.5 mos | 88.2% (0%) | 35.3% (0%) |
Patients with available data | Overall response rate | Complete response rate | negative Minimal residual disease | Cytokine release syndrome | ≥ Grade 3 cytokine release syndrome | Neurotoxicity | ≥ Grade 3 neurotoxicity | Relapse rate | CD22 dim/negative relapse rate |
---|---|---|---|---|---|---|---|---|---|
Age Group | |||||||||
Children (N = 114) | 76% (68–83) | 74% (65–81) | - | 87% (80–92) | 6% (3–12) | 28% (21–37) | - | 36% (18–54) | 16% (0–32) |
Adult (N = 37) | 75% (59–87) | 57% (41–72) | - | 84% (68–93) | 5% (1–19) | 11% (4–25) | - | 6% (0–20) | 3% (0–9) |
p value | 0.94 | 0.05* | - | 0.6 | 0.9 | 0.04* | - | 0.01** | 0.14 |
Bone marrow involvement (B-ALL) | |||||||||
High burden (N = 98) | 74% (65–82) | 63% (43–83) | 66% (55–75) | 86% (78–92) | 7% (3–14) | 25% (17–34) | 1% (0–7) | 23% (6–58) | 8% (1–46) |
Low burden (N = 25) | 81% (66–96) | 76% (59–93) | 68% (48–83) | 88% (69–96) | 4% (1–24) | 32% (17–52) | 4% (1–24) | 40% (23–60) | 12% (4–31) |
p value | 0.22 | 0.54 | 0.82 | 0.81 | 0.6 | 0.46 | 0.32 | 0.37 | 0.73 |
Disease | |||||||||
B-ALL (N = 133) | 76% (69–83) | 72% (65–80) | - | 87% (82–93) | 4% (1–8) | 20% (8–32) | 1% (0–3) | 31% (13–49) | 11% (0–23) |
B cell lymphoma (N = 28) | 86% (73–99) | 64% (47–82) | - | 74% (19–100) | 4% (0–12) | 10% (0–28) | 0% (0–6) | 8% (0–19) | 4% (0–12) |
p value | 0.19 | 0.41 | - | < 0.01** | 0.87 | 0.36 | 0.75 | 0.04* | 0.35 |
Prior CD19 CAR-T therapy | |||||||||
Yes (N = 67) | 75% (65–87) | 73% (62–86) | 45% (16–74) | 76% (62–91) | 9% (3–30) | 0% (0–6) | 0% (0–6) | 19% (0–46) | 24% (9–66) |
No (N = 15) | 76% (58–100) | 79% (58–100) | 62% (22–100) | 83% (62–100) | 13% (3–58) | 0% (0–6) | 0% (0–6) | 29% (5–52) | 20% (7–60) |
p value | 0.76 | 0.64 | 0.5 | 0.59 | 0.72 | 1 | 1 | 0.59 | 0.55 |
Overcoming treatment failure of CD22 CAR-T cells
Clinical trial information | Institution | Dual-targeting strategy | CAR structures | Disease and patients | Prior CD19 CAR-T treatment at baseline | ORR(≥ CR, best response) | Prognosis | CRS at any grade (grade ≥ 3), evaluation criteria | Neurotoxicity at any grade (grade ≥ 3), evaluation criteria |
---|---|---|---|---|---|---|---|---|---|
Observational study ChiCTR-OPN-16008526 [86] | Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology | Sequential infusion without interval (D0-D3) | anti-CD19 scFv (Murine)/4-1BB anti-CD22 scFv (Murine)/4-1BB | R/R B-ALL 51 pts R/R B-cell NHL 38 pts | - | B-ALL: 98% (96%) in 50 evaluable pts B-cell NHL: 72.2% (50%) in 36 evaluable pts | B-ALL: mPFS 13.6 mos, mOS 31 mos B-cell NHL: mPFS 9.9 mos, mOS 18 mos | 95.5%(17.9%) Lee criteria | CRES 13.5% (1.1%) CTCTE criteria |
Observational study ChiCTR-ONC-17013648 [87] | Beijing Boren Hospital | Sequential infusion | FMC63 scFv/4-1BB anti-CD22 scFv (human)/4-1BB | R/R B-ALL 21 pts | 100% (16 CR, 3 PR, 2 relapsed) | 95% (95%) | 18-month OS rate 88.5% 18-month EFS rate 67.5% | 52% (0%) Penn criteria | 0% (0%) CTCTE criteria |
Phase 1 ChiCTR-OIB-17013670 [88] | Beijing Boren Hospital | Sequential infusion | anti-CD19 scFv/4-1BB anti-CD22 scFv/4-1BB | R/R B-ALL 20 pts | - | 100% (100%) | mLFS/mOS not reached 1-year LFS rate 79.5% 1-year OS rate 92.3% | CD19 CAR-T 90% (5%) CD22 CAR-T 75% (0%) | CD19 CAR-T 15% (5%) CD22 CAR-T 15% (0%) |
Phase 2 ChiCTR2000032211 [89] | Multicenter | Coadministration (1:1) | anti-CD19 scFv/4-1BB anti-CD22 scFv/4-1BB | B-ALL 6 pts R/R B-ALL 188 pts B-ALL with isolated EMD 31 pts | - | 99% (99%) | 12-month EFS rate 73.5% | 88% (28.4%) ASTCT criteria | 20.9% (4.0%) ASTCT criteria |
Phase 1 NCT03289455 [93] | Autolus PLC | Bicistronic CAR-T | FMC63 scFv/OX40 LT22 scFv-COMP/4-1BB | R/R B-ALL 15 pts | - | 86.7% ( 86.7%) | - | 80% (0%) Lee criteria | ICANS 26.7% (0%) ASTCT criteria |
Phase 1 (UCAR-T) NCT04227015 [95] | The First Affiliated Hospital, School of Medicine, Zhejiang University | Tantem CAR-T | FMC63 scFv-m971 scFv/4-1BB | R/R B-ALL 6 pts | - | 83.3% (83.3%) | - | 100% (16.7%) | 0% (0%) |
Phase 1 ChiCTR1800015575 [96] | The First Affiliated Hospital, School of Medicine, Zhejiang University | Tantem CAR-T | FMC63 scFv-anti-CD22 scFv(human)/4-1BB | R/R B-cell lymphoma 16 pts | - | 87.5% (62.5%) | 2-year OS rate 77.3% 2-year PFS rate 40.2% mPFS 246 days | 100% (6.3%) ASTCT criteria | 0% (0%) CTCAE criteria |
Phase 1 NCT03185494 [97] | Institute of Basic Medicine, Chinese PLA General Hospital | Tantem CAR-T | m971 scFv-FMC63 scFv/4-1BB | R/R B-ALL 6 pts | - | 100% (100%) | - | 100% (0%) Lee criteria | ICANS 0% (0%) ASTCT criteria |
Phase 1 NCT03233854 [102] | Stanford University School of Medicine | Loop CAR-T | FMC63 VH-m971 VL-m971 VH-FMC63 VL/4-1BB | R/R B-ALL 17 pts R/R LBCL 21 pts | DLBCL 65% | B-ALL: 100% (80%) LBCL: 62% (29%) | - | 76% (5%) Lee criteria | 37% (10.5%) CTCAE criteria |
Phase 1 NCT03919526 [103] | Shanghai General Hospital, Shanghai Jiaotong University School of Medicine | Loop CAR-T | FMC63 VL-m971 VH-m971 VL-FMC63 VH/4-1BB | B-ALL 15 pts | - | 100% (100%) | mRFS/mOS not reached 12-month RFS rate 77% 12-month OS rate 86% | 26.7% (0%) ASTCT criteria | ICANS 0% (0%) ASTCT criteria |