Monoclonal Antibodies Against Myeloid Leukemia Cells: Current Knowledge and Future Directions
Abstract
1. Introduction
2. MAbs in Cancer Therapy: Background and Rationale
2.1. Monospecific Antibodies
2.2. Conjugated Antibodies
2.3. Bispecific Antibodies
3. MAbs in AML
3.1. Unconjugated Antibodies
3.1.1. Anti CD33
3.1.2. Anti CD123 Antibody
3.1.3. Anti CD38 (Daratumumab, Isatuximab)
3.1.4. Anti FLT3
3.2. Conjugated MAbs (ADCs)
3.2.1. Anti-CD33—Gemtuzumab Ozogamicin
3.2.2. Other Anti-CD33 ADCs
3.2.3. Anti-CD123
3.2.4. Anti-CD371 (CLL1, Clec12A)
3.2.5. Anti-FLT3
3.2.6. Anti-CD25
3.2.7. Anti CD30
3.2.8. Anti ASCT2
3.2.9. Radio-Conjugated Antibodies
3.3. Bispecific Antibodies
4. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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1. ELN | ||
Risk | Genetic lesions | |
Favorable | t(8;21); RUNX1::RUNX1T1 | |
inv(16)(p13.1q22); CBFB::MYH11 | ||
Mutated NPM1 without FLT3-ITD bZIP in-frame mutated CEPBA | ||
Intermediate | Mutated NPM1 with FLT3-ITD Wild type NPM1 with FLT3-ITD t(9;11)(p21q23.3); MLLT3::KMT2A Cytogenetics abnormalities not classified as favorable or adverse | |
Adverse | t(6;9)(p23;q34.1); DEK::NUP214 | |
t(v;11q23.3);KMT2A rearranged | ||
t(9:22)(q34.1); q11.2); BCR-ABL | ||
inv (3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); MECOM (EVI1) -5 or del(5q); -7; -17/abnormality (17p) Complex karyotype (≥3), Monosomal karyotype Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSF2 Mutated TP53 | ||
2. NCCN | ||
Risk | Cytogenetics | Molecular abnormalities |
Better | Inversion (16) or t(16;16) t(8;21) t(15;17) | Normal cytogenetics: NPM1 mutation without FLT3-ITD; bZIP in frame CEPBA mutation |
Intermediate | Normal cytogenetics Trisomy 8alone t(9;11) Other not defined | Mutated -NPM1 and FLT3-ITD Wild type NPM1 and wild type FLT3 |
Poor | Complex (≥3 clonal chromosomal abn) Monosomal karyotype -5; 5q-;-7; 7q- -11q23-non translocation (9;11) inv(3), t(3;3) t(6;9) or t(9;22) or t(8;16) | Mutated TP53 Mutated RUNX1, ASXL1, BCOR, EZH2, SF3B1,SRSF2, STAG2, U2AF11nad/or ZRSR2 Wild type NPM1 and FLT3-ITD (high allelic ratio) |
Trial | Patients (N) | Age (Range) | GO Dose/Schedule | CR (%) | RFS | OS | VOD/SOS (N)/ ≥3 Hepatic Toxicity (%) | Ref |
---|---|---|---|---|---|---|---|---|
SWOG S0106 | 595 | 18–60 | 6 mg/m2 on D4 | 75 | 5-yrs 43% | 5-yrs 46% | 0/NA | [94] |
GOLEAMS Aml 2006 | 254 | 18–60 | 6 mg/m2 on D1 | 92 | 3-yrs 51% | 3-yrs 53% | 4/23 | [98] |
MRC AML15 | 1099 | 18–59 | 3 mg/m2 on D1 | 82 | 5-yrs 39% | 5-yrs 43% | 0/NA | [99] |
ALFA-0701 | 278 | 50–70 | 3 mg/m2 on D1,4,7 | 81 | 2-yrs 50% | 2-yrs 53% | 2/6 | [97] |
NCRI AML16 | 1115 | 51–84 | 3 mg/m2 on D1 | 62 | 3-yrs 21% | 3-yrs 25% | 0/17 | [100] |
GIMEMA AML19 | 237 | 61–75 | 6 mg/m2 on D1, 3 mg/m2 on D8, 2 mg/m2 monthly x8 | 15 | 1-yrs 10% | 3-yrs 24% | 0/7 | [101] |
Trial Identifier | Title | Phase | Status |
---|---|---|---|
NCT03904251 | CPX-351+GO in R/R AML | 1 | Completed |
NCT04070768 | Venetoclax+GO in R/R CD33 AML | 1b | Completed |
NCT03848754 | Pracinostat+GO (PRAGO) in R/R AML | 1 | Completed |
NCT00766116 | Azacytidine+GO in R/R AML | 1/2 | Completed |
NCT02182596 | DNR+AraC and Fractioned GO in AML at first relapse | 1/2 | Completed |
NCT03839446 | Mitoxantrone, Etoposide and GO for AML refractory to Initial Standard Induction Therapy | 2 | Completed |
NCT00044733 | GO in AML relapsed after autologous or allogeneic SCT | 2 | Completed |
NCT05558124 | CPX-351 in combination with GO in newly diagnosed AML | 1 | Recruiting |
NCT05716009 | Tagraxofisp-erzs, an IL-3 Diphteria Fusion Protein in combination with GO in R/R AML | 1 | Recruiting |
NCT04849910 | Allogeneic engineered HCT lacking the CD33 protein, and post HCT treatment with GO, for CD33+Aml or MDS | 1/2 | Recruiting |
NCT00801489 | GO+Fluda+AraC+filgrastim-sndz+idarubicin in newly diagnosed AML and HR-MDS | 2 | Recruiting |
NCT03672539 | CPX-351 and GO in R/R AML or HRMDS | 2 | Recruiting |
NCT04050280 | Fractioned GO+Cladribrine +AraC+ G-CSF (CLAG-G) in persistent, R/RAML | 2 | Recruiting |
NCT03737955 | Fractioned GO in treating MRD in AML | 2 | Recruiting |
NCT04168502 | GO chemotherapy MRD levels; adult untreated, de novo favorable/intermediate risk AML | 3 | Recruiting |
NCT03900949 | GO and Midostaurin combination with standard Cytarabine and Daunorubi Midostaurin as a novel approach to treating patients with newly diagnosed FLT3 mutated AML | 1 | Active, NR |
NCT04385290 | Midostaurin +GO in first line standard therapy for Acute Myeloid Leukemia (MOSAIC) | 1/2 | Active, NR |
NCT00658814 | Azacitidine and GO in Treating Older Patients with previously untreated AML | 2 | Active, NR |
NCT03374332 | Fractioned GO followed by non-engraftment Donor Leukocyte infusion for R/R AML | 2 | Active, NR |
Target | Phase | Agent | Population | Donor | Trial Identifier |
---|---|---|---|---|---|
CD45 | I/II | 211-At-BC8B10 Fluda/Cy/2GyTBI | ≥18 R/R AML | Haplo | NCT03670966 |
CD45 | I/II | 211-At-BC8B10 Fludarabine/TBI | 18–75 (adult-older) AML, mixed AL, HR-MDS | HLA MRD or MUD | NCT03128034 |
CD33 | I | 225Ac-Lintuzumab+ CLAG-M | ≥18 R/R AML | // | NCT03441048 |
CD33 | I/II | 225Ac-Lintuzumab+ Venetoclax | ≥18 R/R AML (including secondary) | // | NCT03867682 |
CD25 | I | 90-Y-DOTA-Basiliximab Flu/Mel/TBI | 18–60 high risk AML in CR or with sensitive disease | Allo-SCT | NCT05139004 |
Antibody Construct | Target | Phase | Study Population | Response | Toxicity | Reference |
---|---|---|---|---|---|---|
BiTE | CD3xCD33 | I | R/R highly treated | CR: 3/9 evaluable PR: 1/9 evaluable Blast reduction: 17/27 evaluable | Grade ≥3 febrile neutropenia (9/30, 30%) Grade 2 CRS (1/30) Therapy-related deaths: 0 | [153] |
CD3xCD33 | I | R/R adult AML | CR: 8/60 evaluable Blast reduction: 37%of non-responders | CRS: 78% (grade3/4: 10%) Infusion reaction: 30% Therapy-related deaths: 0 | [154] | |
CD3xCD33 | I | R/R adult AML, MDS | No responders | ≥1dose-limiting toxicity: 16% ≥1CRS: 42%, ≥ICANS: 7% Hematologic toxicity: 11% Therapy-related deaths: 16 | [155] | |
CD3xCD123 | I | R/R AML, MDS | CR: 2/8 evaluable SD: 6/8 evaluable | CRS: 10%, ICANS: 10% Infusion reaction: 28% Therapy-related deaths: 0 | [156] | |
CD3xCD123 | I | Adult de novo/secondary AML; B-ALL, BPDN, BP-CML | ORR (MLFS or better): 9% | ≥1dose-limiting toxicity: 16/120 CRS: 59%, ICANS: 2.5% Hematologic toxicity: 51% Therapy-related deaths: 8 | [157] | |
CD3xCD38 | I | R/R adult AML CD38+ | MRD neg-CR:2 PR:2 | Grade1/2 CRS: 62% Grade3/4 anemia: 8%, neutropenia: 15%, thrombocytopenia: 23% Therapy-related deaths: 0 | [150] | |
CD3xSurvivin peptide-targeting T-cell receptor | I | R/R Adult AML HLA-A2:01 restricted, NSCL cancer | PR: 1 AML | CRS: 13% ≥Grade3 AEs: 73% Therapy-related deaths: 0 | [151] | |
DART | CD3xCD123 | I/II | R/R Adult AML | CR: 26.7%, ORR 30% of 30 evaluable. mOS: 10.2 months | CRS 34%, grade ≥ 3 cytopenia 10%, peripheral edema 40.9%, Therapy-related deaths: 0 | [158] |
TriKE | CD16/IL15/CD33 | I | R/R Adult CD33+AML, HR MDS | SD: 2 | No toxicities reported Therapy-related deaths: 0 | [152] |
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Damiani, D.; Tiribelli, M. Monoclonal Antibodies Against Myeloid Leukemia Cells: Current Knowledge and Future Directions. Int. J. Mol. Sci. 2025, 26, 4571. https://doi.org/10.3390/ijms26104571
Damiani D, Tiribelli M. Monoclonal Antibodies Against Myeloid Leukemia Cells: Current Knowledge and Future Directions. International Journal of Molecular Sciences. 2025; 26(10):4571. https://doi.org/10.3390/ijms26104571
Chicago/Turabian StyleDamiani, Daniela, and Mario Tiribelli. 2025. "Monoclonal Antibodies Against Myeloid Leukemia Cells: Current Knowledge and Future Directions" International Journal of Molecular Sciences 26, no. 10: 4571. https://doi.org/10.3390/ijms26104571
APA StyleDamiani, D., & Tiribelli, M. (2025). Monoclonal Antibodies Against Myeloid Leukemia Cells: Current Knowledge and Future Directions. International Journal of Molecular Sciences, 26(10), 4571. https://doi.org/10.3390/ijms26104571