Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils
Abstract
:Simple Summary
Abstract
1. Introduction
2. Neutrophils and Their Role in Cancer
3. Cytotoxic Effector Functions of Neutrophils
4. CD47-SIRPα as an Innate Immune Checkpoint in Neutrophil-Mediated Tumor Killing
4.1. SIRPα Signaling
4.2. Neutrophil Effector Functions Influenced by CD47-SIRPα
4.3. The Innate Immune Checkpoint CD47-SIRPα in Cancer
5. Targeting CD47-SIRPα to Potentiate Antibody Therapy
5.1. CD47-Targeting Agents
5.2. Anti-SIRPα mAbs
5.3. Alternative Ways to Disrupt CD47-SIRPα Interactions
6. Conclusions
Anti-CD47 mAbs | |||||||||
---|---|---|---|---|---|---|---|---|---|
Compound | Type | Phase | Trial Identifier | Name | Indication | Treatment | Results | Ref | |
Toxicity (≥Grade 3) | ORR (DCR) | ||||||||
Magrolimab/GS-4721/ (Hu5F9-G4) | anti-CD47 IgG4 | 1/1b | NCT02678338 | CAMELLIA | r/r AML and hrMDS | Mono | 72% anemia 6% lymphopenia | AML = 0% (56%) | [196,236] |
1 | NCT03248479 | AML (65% TP53 mut) | +Azacitidine | 31% anemia 19% hyperbilirubinemia 19% neutropenia 17% thrombocytopenia | 65% (97%) | [198,199,200] | |||
int/high risk MDS (13% TP53 mut) | +Azacitidine | 38% anemia 19% neutropenia 18% thrombocytopenia | 91% (100%) | [198,199,200] | |||||
1 | NCT02216409 | Solid cancer | Mono | 18% lymphopenia 14% anemia 7% Hyperbilirubinemia | 2/44 (OvC and FTC) | [195] | |||
1b/2 | NCT02953782 | CRC KRAS wt/mut | +Cetuximab | 12% anemia 12% hyperbilirubinemia | wtKRAS = 6% (50%) mKRAS = 0% (38%) | [237] | |||
1b/2 | NCT02953509 | NHL | +Rituximab | 42% anemia 15% neutropenia 36% infusion reactions | NHL = 45% (62%) Indolent = 61% (85%) DLBCL = 36% (48%) | [193,194] | |||
NHL | +Rituximab + Gemcitabine + Oxaliplatin | [192,193,194] | |||||||
1 | NCT03558139 | Ovarian cancer | +Avelumab | ||||||
1b/2 | NCT03869190 | MORPEUS-UC | Urothelial & Bladder cancer | +Atezolizumab | |||||
1b | NCT03922477 | AML | +Atezolizumab | ||||||
1 | NCT03527147 | PRISM | NHL | +Rituximab + Acalabrutinib | |||||
2 | NCT04788043 | HL | +Pembrolizumab | ||||||
1 | NCT04599634 | VENOM | r/r indNHL/CLL | +Obinutuzumab + Venetoclax | |||||
1 | NCT04751383 | High-risk & rrNeuroblastoma/rOsteosarcoma | +Dinutuximab | ||||||
+Dinutuximab + surgery | |||||||||
1b/2 | NCT04541017 | CTCL (Myc. Fungoides & Sezary Syndr.) | +Docetaxel + Mogamilizumab | ||||||
Mogamilizumab mono | |||||||||
2 | NCT04827576 | Solid (mNSCLC, mSCLC, mUC) | Mono | ||||||
3 | NCT04313881 | ENHANCE | Untreated hrMDS | +Azacitidine | |||||
Azacitidine mono | |||||||||
3 | NCT05079230 | ENHANCE-3 | Untreated AML | +Azacitidine + Venetoclax | |||||
Azacitidine + Venetoclax | |||||||||
1b/2 | NCT04435691 | r/r and nd AML | +Azacitidine + Venetoclax | ||||||
2 | NCT04958785 | tnmBC | +Paclitaxel- + Nab paclitaxel | ||||||
+Sacituzumab govitecan | |||||||||
2 | NCT04892446 | r/r MM | +Daratumumab | ||||||
+Pomalidomide + Dexamethasone | |||||||||
+Bortezomib + Dexamethasone | |||||||||
3 | NCT04778397 | ENHANCE-2 | untreated T53mut AML | +Azacitidine | |||||
phys choice | |||||||||
2 | NCT04854499 | untreated HNSCC | +Pembrolizumab | ||||||
+Pembrolizumab + chemo/Docetaxel | |||||||||
2 | NCT04778410 | newly diagnosed or r/r AML | +Azacitidine + Venetoclax | ||||||
+MEC chemo | |||||||||
+CC-486 | |||||||||
1 | NCT05169944 | Malignant brain cancer (children & adults) | Mono | ||||||
CC90002 | anti-CD47 IgG4PE | 1 | NCT02641002 | r/r AML and hrMDS | Mono | 36% feb neutropenia 32% thrombocytopenia 29% anemia 18% neutropenia 11% hypokalemia | AML = 0/14 (0/14) MDS = 0/3 (2/3) | [201,238] | |
1 | NCT02367196 | Solid cancer/MM/NHL | +/− Rituximab | 38% neutropenia | NHL = 13% (25%) | [203] | |||
Letaplimab/IBI188 | anti-CD47 IgG4 | 1 | NCT03763149 | Solid tumors and lymphomas | Mono | 1/20 anemia 1/20 hyperbilirubinemia 1/20 thrombocytopenia | [205] | ||
1/1b | NCT03717103 | Solid tumors and lymphomas | Mono | ||||||
+Rituximab | |||||||||
1b | NCT04861948 | Solid tumors (Lung adenocar., Osteosarc., Soft tissue sarc.) | +IBI188 (Anti-PD1)/chemo + Bevacizumab/GM-CSF | ||||||
1 | NCT04511975 | newly diagnosed hrMDS | +Azacitidine | ||||||
1b | NCT04485052 | newly diagnosed or rrAML | +Azacitidine | ||||||
1b | NCT04485065 | newly diagnosed hrMDS | +Azacitidine | ||||||
IBI322 | CD47/PDL1 BsAb IgG4 | 1a | NCT04338659 | Solid tumors | Mono | ||||
1/1b | NCT04328831 | Solid tumors | Mono | ||||||
1/1b | NCT04912466 | Hematologic cancer | Mono | ||||||
1a/1b | NCT04795128 | Hematologic cancer | Mono | ||||||
1a/1b | NCT05148442 | r/r AML and r/r MDS | +Azacitidine | ||||||
AO176 | anti-CD47 IgG2 | 1/2 | NCT03834948 | Solid tumors | Mono | ||||
+Paclitaxel/Pembrolizumab | |||||||||
1/2 | NCT04445701 | Multiple myeloma | Mono | ||||||
+DEX/Bortezomib | |||||||||
SRF231 | anti-CD47 IgG4 | 1/1b | NCT03512340 | Solid and hematologic cancer | Mono | 1/25 feb neutropenia 1/25 hemolysis 1/21 thrombocytopenia 1/21 elevated lipase/amylase | 0% | [239] | |
TG1801/NI-1701 | CD47/CD19 BsAb IgG4 | 1 | NCT03804996 | B lymphoma | Mono | ||||
+Ublituximab | |||||||||
1/1b | NCT04806035 | CD20+ NHL and CLL | Mono | ||||||
+Ublituximab | |||||||||
Lemzoparlimab/TJ011133/ TJC4 | anti-CD47 IgG4 | 1 | NCT03934814 | Melanoma | Mono | 5% elevated lipase | 1/20 (4/20) | [206] | |
NHL | +Rituximab | 11% neutropenia | NHL = 71% Indolent = 75% DLBCL = 50% | [207] | |||||
Solid and hematologic cancer | Mono | ||||||||
+Rituximab | |||||||||
+Pembrolizumab | |||||||||
1/2a | NCT04202003 | AML and ir/hrMDS | +Azacitidine | 1/5 thrombocytopenia | 1/5 | [208] | |||
1 | NCT04912063 | untreated AML and hrMDS | +Azacitidine + Venetoclax | ||||||
1 | NCT04895410 | r/r MM | Mono | ||||||
+Pomalidomide + Dexamethasone | |||||||||
+Carfilzomib + Dexamethasone | |||||||||
+Daratumumab + Dexamethasone | |||||||||
1/2 | NCT05148533 | advanced, melanoma, GC, HNSCC | +Toripalimab | ||||||
ZL1201 | anti-CD47 IgG4 | 1 | NCT04257617 | Solid cancer and lymphoma | Mono | ||||
HX009 | CD47/PD1 BsAb IgG4 | 1 | NCT04097769 | Solid cancer | Mono | ||||
2 | NCT04886271 | Solid cancer | Mono | ||||||
1/2 | NCT05189093 | r/r Lymphoma (NHL, Hodgkin, PTCL) | Mono | ||||||
AK117 | anti-CD47 IgG4 | 1 | NCT04349969 | Solid cancer and NHL | Mono | ||||
1/2 | NCT04900350 | MDS | +Azacitidine | ||||||
1 | NCT04728334 | r/r Solid cancer and NHL | Mono | ||||||
1b/2 | NCT04980885 | AML | +Azacitidine | ||||||
1b/2 | NCT05214482 | adv. Solid cancer | +AK112 (anti-PD-1/VEGF BsAb) +/− chemo | ||||||
1b/2 | NCT05229497 | adv. Solid cancer (Ph2: Adv HNSCC) | + AK112 (anti-PD-1/VEGF BsAb) + chemo | ||||||
1b/2 | NCT05235542 | adv. solid cancer (Ph2: Adv GEJ or Esoph Cancer) | + AK104 (anti-PD-1/CTLA4 BsAb) +/− chemo | ||||||
IMC-002 | anti-CD47 IgG4 | 1 | NCT04306224 | Solid and hematological | Mono | ||||
1 | NCT05276310 | adv. solid cancer | |||||||
SGN-CD47M | anti-CD47 ADC | 1 | NCT03957096 | Solid cancer | Mono | ||||
PF-07257876 | CD47/PDL1 BsAb IgG4 | 1 | NCT04881045 | NSCLC, SCCHN, ovarian cancer | Mono | ||||
TQB2928 | CD47-SIRPα NME | 1 | NCT04854681 | Solid and hematological cancer | Mono | ||||
H4C1/ SHR-1603 | anti-CD47 | 1/2 | NCT04588324 | Solid cancer | +SHR2150 (TLR7 agonist) + chemo + Anti-PD-1 | ||||
STI-6643 | anti-CD47 IgG4 (228P) | 1 | NCT04900519 | Solid cancer | Mono | ||||
sB24M | anti-CD47/TNF-α | 1 | NCT04895566 | Severe Pyoderma | Mono (local application) | ||||
IMM0306 | CD47/CD20 BsAb IgG1 | 1 | NCT04746131 | NHL | Mono | ||||
SHR-1603 | anti-CD47 IgG4 | 1 | NCT03722186 | Solid cancer and rrLymphoma | Mono | ||||
anti-CD47 | anti-CD47 | 1 | NCT05266274 | recurr AML after transplantation | +Azacitidine | ||||
Gentulizumab | anti-CD47 | 1 | NCT05221385 | Adv solid cancer and NHL | Mono | ||||
1a | NCT05263271 | r/r AML and MDS | Mono | ||||||
TQB2928 | anti-CD47 | 1 | NCT05192512 | Adv solid cancer and lymphoma | Mono | ||||
BAT7104 | CD47/PDL1 BsAb | 1 | NCT05200013 | Adv solid cancer | Mono | ||||
SG2501 | CD47/CD38 BsAb | 1 | NCT05293912 | r/r hematologic malignancies | Mono |
SIRPα-Fc | |||||||||
---|---|---|---|---|---|---|---|---|---|
Compound | Type | Phase | Trial Identifier | Name | Indication | Treatment | Results | Ref | |
Toxicity (≥Grade 3) | ORR (DCR) | ||||||||
TTI-621 | SIRPα-IgG1Fc | 1/1b | NCT02663518 | Lymphoma | Mono | 9% neutropenia 20% thrombocytopenia 9% anemia | NHL = 10% (62%) Indolent = 0% (78%) DLBCL = 29% (29–50%) | [211,240] | |
+Rituximab | 9% neutropenia 20% thrombocytopenia 9% anemia | NHL = 23% (62%) Indolent = 50% (100%) DLBCL = 20% (57%) CTCL = 18% PTCL = 26% Hodgkin = 13% (63%) | [211,241] | ||||||
+Nivolumab | 9% neutropenia 20% thrombocytopenia 9% anemia | NHL = 50% (50%) | [211] | ||||||
1 | NCT02890368 | CTCL | Mono | None reported | CTCL = 90% (34%) | [212] | |||
Solid tumors, melanoma, breast ca, soft tissue sarcoma, CTCL | Mono | ||||||||
+Anti-PD-1/PD-L1 (nivolumab, pembrolizumab, durvalumab, avelumab, or atezolizumab) | |||||||||
+PEG-IFN-α2a | |||||||||
+T-VEC | |||||||||
+radiation | |||||||||
1/2 | NCT04996004 | Leiomyosarcoma | +Doxorubicin | ||||||
TTI-622 | SIRPα-IgG4Fc | 1/1b | NCT03530683 | r/r NHL | Mono | 9% neutropenia 5% thrombocytopenia 2% anemia | NHL = 24% (53%) Indolent = 33% (33%) DLBCL = 21% (43%) | ||
r/r NHL, r/r MM, newly diagnosed AML T53wt/mut | Mono | ||||||||
+Azacitidine +/− Venetoclax | |||||||||
+Carfilzomib + Dexamethasone | |||||||||
1/2 | NCT05261490 | OvC | +Pegylated Doxoribicin | ||||||
Both TTI-621 and TTI-622 | 1 | NCT05139225 | r/r MM | +Daratumumab Hyaloronidase-fihj | |||||
ALX-148/Evorpacept | affinity-enhanced SIRPα-FcDEAD | 1 | NCT03013218 | ASPEN-1 | Hematologic and SCLC | +Rituximab | 6% neutropenia 3% anemia | NHL = 48% (60%) Indolent = 61% (91%) DLBCL = 38% (48%) | [242,243] |
Mono | |||||||||
+Nivolumab | |||||||||
Gastric cancer | +Trastuzumab + Ramucirumab + Paclitaxel | 44% neutropenia 33% hypertension 22% anemia | 72% (89%) | [244,245,246] | |||||
+Trastuzumab | 6% thrombocytopenia 6% neutropenia <5% feb neutropenia WBC count | 21% (47%) | [217,244,245] | ||||||
HNSCC | +Pembrolizumab + 5FU/Platinum | 38% neutropenia 31% anemia | 39% (89%) | [245,246] | |||||
+Pembrolizumab | Rare (<5%) anemia, thrombocytopenia, AIHA, neutropenia, pancytopenia | 20–40% | [217,245,246] | ||||||
NSCLC | +Pembrolizumab | Rare (<5%) anemia, thrombocytopenia, AIHA, neutropenia, pancytopenia | 5% (40%) | [217] | |||||
1/2 | NCT04417517 | ASPEN-2 | untreated or r/r hrMDS | +Azacitidine | 18% neutropenia 18% feb neutropenia 14% thrombocytopenia 9% anemia | 55% (80%) | [247] | ||
2/3 | NCT05002127 | ASPEN-6 | HER-2+ GC/GJC | +Trastuzumab + Ramucirumab + Paclitaxel | |||||
Trastuzumab + Ramucirumab + Paclitaxel | |||||||||
Ramucirumab + Paclitaxel | |||||||||
1/2 | NCT04755244 | ASPEN-5 | AML | +Venetoclax + Azacitidine | |||||
2 | NCT04675333 | ASPEN-4 | HNSCC | +Pembrolizumab + 5FU/Platinum | |||||
2 | NCT04675294 | ASPEN-3 | HNSCC | +Pembrolizumab | |||||
Pembrolizumab mono | |||||||||
2 | NCT05167409 | Microsatellite stable rCRC | +Cetuximab + Pembrolizumab | ||||||
1/2 | NCT05025800 | NHL | +Rituximab + Lenolidamide | ||||||
1/2 | NCT05027139 | metastatic/inoperable HER-2+ BC/GEC cancer | +Zanidatamab (anti-HER-2 BsAb) | ||||||
2 | NCT05167409 | MSS CRC | +Cetuximab + Pembrolizumab | ||||||
SL-172154 | SIRPα-Fc-CD40L | 1 | NCT04406623 | Ovarian, Fallopian tube, peritoneal cancer | Mono | ||||
1 | NCT04502888 | HNSCC & CSCC | Mono (intratumorally) | ||||||
CPO107/JMT601 | SIRPα ECD/anti-CD20 BsAb IgG1 | 1/2 | NCT04853329 | NHL | Mono | ||||
IMM01 | SIRPα-Fc | 1/2 | NCT05140811 | AML and MDS | +Azacitidine | ||||
IMM2902 | SIRPαECD/anti-HER-2 | 1 | NCT05076591 | HER-2+ BC and GC | Mono | ||||
DSP107 | SIRPα-41BB fusion | 1/2 | NCT04440735 | Solid/NSCLC | Mono | ||||
+Atezolizumab |
Anti-SIRPα mAbs | |||||||||
---|---|---|---|---|---|---|---|---|---|
Compound | Type | Phase | Trial Identifier | Name | Indication | Treatment | Results | Ref | |
Toxicity (≥Grade 3) | ORR (DCR) | ||||||||
GS-0189 | anti-SIRPα IgG1 N297A | 1 | NCT04502706 | NHL | Mono | ||||
+Rituximab | |||||||||
CC-95251 | anti-SIRPα IgG1 K322A | 1 | NCT03783403 | Solid and hematologic cancer | Mono | 53% neutropenia 6% thrombocytopenia | 56% (56%) | [219] | |
+Cetuximab/Rituximab | |||||||||
1 | NCT05168202 | r/r AML/MDS | Mono | ||||||
+azacitidine | |||||||||
BI765063/ OSE-172 | anti-SIRPαBIT IgG4 S229P-L445P | 1 | NCT03990233 | Solid cancer | Mono | None reported | 1/50 PR (HCC) | [220] | |
+BI754091 (anti-PD-1) | 1 rash maculo-papular | 19% (25%) | [220] | ||||||
1 | NCT04653142 | Solid cancer | Mono | ||||||
+BI754091 (anti-PD-1) | |||||||||
1 | NCT05068102 | Melanoma, HNSCC, NSCLC | Mono (Biodistribution, imaging with 89Zr-BI765063) | ||||||
1 | NCT05249426 | HNSCC | +BI754091 (anti-PD-1) +/− Cetuximab/chemo | ||||||
HCC | +BI754091 (anti-PD-1) +/− BI836880 (anti-VEGF/Ang2 BsAb) |
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Name | FcγRI (CD64) | FcγRIIa (CD32a) | FcγRIIb (CD32b) | FcγRIIc (CD32c) | FcγRIIIa (CD16a) | FcγRIIIb (CD16b) | FcαRI (CD89) |
---|---|---|---|---|---|---|---|
Structure | |||||||
Affinity | High | Low | Low | Low | Low | Low | High |
Expression on neutrophils | Induced 1 | + | Genotype-dependent 2 | Genotype-dependent 3 | −/+ 4 | + | + |
Class | Activation | Activation | Inhibition | Activation | Decoy | Activation |
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Behrens, L.M.; van den Berg, T.K.; van Egmond, M. Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils. Cancers 2022, 14, 3366. https://doi.org/10.3390/cancers14143366
Behrens LM, van den Berg TK, van Egmond M. Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils. Cancers. 2022; 14(14):3366. https://doi.org/10.3390/cancers14143366
Chicago/Turabian StyleBehrens, Leonie M., Timo K. van den Berg, and Marjolein van Egmond. 2022. "Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils" Cancers 14, no. 14: 3366. https://doi.org/10.3390/cancers14143366