Antibody Targeted Therapy for Acute myeloid leukemia and myelodysplastic syndrome
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Antibody Targeted Therapy for Acute myeloid leukemia ( AML ) and myelodysplastic syndrome ( MDS ).
Acute myeloid leukemia ( AML ) and myelodysplastic syndrome ( MDS ) remain an unmet clinical need.
According to the revised International Prognostic Scoring Scale ( IPSS-R ), the prognosis of high-risk MDS and AML with unfavorable features such as age, previous myeloid disease, adverse genetic risk and concurrent gene mutations remains dismal.
In fact, the median overall survival ( OS ) of MDS patients at very high risk for IPSS-R was only 0.8 years, while the five-year survival rate for new-onset AML patients in younger patients was 40%, greater than that in patients aged 70 years.
The annual survival rate is less than 5%, underscoring the urgent need for new therapeutic strategies.
Altered immune responses play an important role in the pathogenesis of AML/MDS, which provides new options for immunotherapy.
Currently, among immune system regulators, CD47, immune checkpoints, and toll-like receptor 2 ( TLR2 ) are major targets in AML and MDS.
Multiple antibody drug formats for several other surface molecules ( i.e., CD33, CD123, CD45, and CD70 ), including naked antibodies, bispecific T cell binders, trispecific antibodies, and ADCs, are being investigated as monotherapy or in combination with other Drugs are used in combination.
They represent the future of AML and high-risk MDS treatment.
Immune System Dysfunction in AML/MDS
Dysregulation of the immune system may affect the pathogenesis of AML and MDS through multiple pathways.
The bone marrow microenvironment in MDS is characterized by perturbations of adaptive and innate immune effector cells, with some cell subtypes, such as type 1 innate lymphoid cells ( ILC1 ), decreased and others, such as myeloid-derived suppressor cells ( MDSCs ), increased .
MDSCs enhance the stimulation of danger-associated molecular patterns of caspase-1, which promotes cell death by secreting granzyme B and IL-10 and by promoting signaling of toll-like receptors ( TLRs ), CD33, and CXCR2.
Dysfunction of ILC1 has also been observed in AML.
AML cells alter the immune microenvironment through multiple mechanisms, including immune checkpoint upregulation and human leukocyte antigen ( HLA ) class I and II downregulation, thereby evading immune surveillance.
Taken together, these evidences suggest that alterations in innate and adaptive immune responses play an important role in the pathogenesis of AML and MDS, which also provides us with potential new targets for immunotherapy.
Potential therapeutic targets for AML/MDS
Immune system modulators are emerging as major targets for immunotherapy in hematological malignancies, including CD47 , immune checkpoints, and TLR2 .
In addition, other surface molecules of AML and MDS cells are currently being used as therapeutic targets for mAbs, including CD33 , CD123 , CD45 , and CD70 .
CD47
CD-47 is a transmembrane protein whose interaction with signal regulatory protein α ( SIRPα ) determines the regulation of inhibition of macrophage-mediated phagocytosis.
Anti-CD47 mAb blocks this interaction, thereby promoting the killing of tumor cells by macrophages and the cross-priming of tumor-specific cytotoxic T cells, thereby activating the adaptive immune response.
CTLA-4
CTLA-4 ( CD152 ), is a co-receptor of the T cell receptor ( TCR ) belonging to the immunoglobulin superfamily .
It is expressed on CD4+ and CD8+ T lymphocytes and has inhibitory immunomodulatory effects. CTLA-4 ligands are CD80 ( B7-1 ) and CD86 ( B7-2 ) expressed on antigen-presenting cells ( APCs ).
Binding of CTLA-4 to its ligand blocks phosphorylation of the TCR-associated zeta chain and delivers an inhibitory signal to lymphocytes.
Thus, blocking the activity of CTLA-4 increases the ability of the immune system to recognize and destroy tumor cells.
PD-1/PD-L1
PD-1 ( CD279 ), a co-inhibitory molecule belonging to the Ig superfamily, is expressed on activated T cells, B cells and myeloid cells.
Binding of PD-1 to the ligand PD-L1 ( CD274 ) expressed on the surface of tumor cells and MDSCs leads to attenuation of TCR-mediated signaling.
This pathway simultaneously regulates the development, maintenance and function of induced T-reg cells.
TIM-3
TIM3, a co-inhibitory receptor expressed on CD4+ T cells and CD8+ T cells, triggers cell death by interacting with the ligand galectin-9 as a negative regulator of these lymphocyte populations.
TIM-3 is expressed on immune and leukemic stem cells ( LSCs ), but not normal hematopoietic stem cells ( HSCs ); its interaction with galectin-9 promotes self-renewal of LSCs, making it an effective candidate for MDS/AML Foreground target.
TLR-2
TLR2, also known as CD282, is a member of the Toll-like receptor family that is expressed on the surface of various cells, including HSCs and hematopoietic progenitor cells ( HSPCs ), and plays fundamental roles in pathogen recognition and innate immune activation.
Overexpression of TLR2 leads to upregulation of the IL-8 molecular pathway, which is often dysregulated in MDS patients.
CD33
CD33, a sialic acid-binding Ig-like lectin ( Siglec ), is expressed as a transmembrane protein on the surface of malignant AML blasts and MDSCs in MDS, but not on HSCs. These features make CD33 an ideal target for immunotherapy.
CD123
CD123 is the alpha chain of the IL-3 receptor ( IL-3Rα ) expressed on myeloid pluripotent stem progenitor cells .
Its interaction with IL-3 induces intracellular tyrosine phosphorylation through JAK-2, promoting the proliferation and differentiation of myeloid cells.
IL-3Rα is expressed on AML blasts and is overexpressed in leukemic cells compared with normal HSCs, making it a promising therapeutic target.
CD45
Protein tyrosine phosphatase receptor type C, also known as CD45, is a transmembrane protein present in almost all differentiated hematopoietic cell subtypes.
CD45 is a signaling molecule that regulates a variety of cellular processes, including cell growth, mitotic cell cycle, and cell differentiation.
CD45 is ubiquitously expressed on AML blasts and has become a target of radioimmunotherapy as part of a preconditioning regimen for allogeneic hematopoietic stem cell transplantation ( HSCT ), exerting its effects by delivering a cytotoxic payload to leukemic cells.
CD70
Although primarily a lymphoid marker, CD70 is also expressed in myeloid leukemia cells and is absent or expressed at low levels in normal myeloid cells.
The interaction between CD70 and its ligand CD27 in AML stem cells induces the activation of molecular signaling pathways, including Wnt, JAK/STAT, Hedgehog, and TGF-β signaling, and promotes cell division.
Targeted immunotherapy for AML
Several monoclonal antibody drugs that target immune modulatory molecules ( CD47 and immune checkpoints ) and other membrane antigens ( CD33, CD123, CD45 and CD70 ).
CD47
Currently, an ongoing phase Ib clinical trial ( NCT03248479 ) of magrolimab targeting CD47 includes 25 untreated AML patients who are not candidates for high-dose induction chemotherapy.
The combination of magrolimab and HMA-azacytidine ( AZA ) had an overall response rate ( ORR ) of 69%, of which 50% were complete remissions ( CR ) or complete remissions with incomplete hematologic recovery ( CRi ).
Treatment-related adverse events included anemia ( 37% ), neutropenia ( 26% ), and thrombocytopenia ( 26% ).
In addition to magrolimab, other anti-CD47-targeted drugs are also under investigation.
Evorpacept ( ALX148 ) is a fusion protein consisting of a CD47-targeting modified SIRPαD1 domain fused to an IgG1 Fc fragment.
The molecule is currently in a phase I/II clinical trial ( NCT04755244 ) in combination with the BCL2 inhibitor venetoclax and AZA in R/R AML who were untreated or ineligible for standard induction chemotherapy.
Immune checkpoint
Several immune checkpoint inhibitors are currently being investigated in AML alone or in combination with standard therapies.
Data from phase I studies suggest that these mAbs have limited efficacy when used as monotherapy and may have synergistic effects when combined with HMAs. A phase I/IB study ( NCT01822509 ) tested ipilimumab in patients with R/R AML after allogeneic HSCT.
Sustained responses ( >1 year ) were observed in 4 of 22 patients .
Of note, 21% of patients had immune-mediated toxic effects.
Sabatolimab ( MBG453 ), a novel antibody targeting TIM-3, is in a phase Ib trial ( NCT03066648 ).
Among 34 newly diagnosed AML patients who were not candidates for standard chemotherapy or HSCT, the ORR was 41.2%, including 8 CRs, 3 CRi, and 3 PRs.
Common ≥3 treatment-related adverse events included thrombocytopenia ( 45.8% ), neutropenia ( 50% ), febrile neutropenia ( 29.2% ), anemia ( 27.1% ), and pneumonia ( 10.4% ).
Overall, this study suggests that TIM-3 may be a new promising therapeutic target.
CD33
In 2000, the FDA approved gemtuzumab ozogamicin ( GO ), a CD33-targeting ADC, for CD33+ relapsed AML ineligible for chemotherapy.
However, in 2010, GO was withdrawn due to unacceptable toxicities, including major bleeding events, infections, and/or acute respiratory distress syndrome.
Subsequently, the phase III multicenter randomized trial of ALFA-0701 showed that GO was adequately tolerated if administered in divided doses.
Therefore, in 2017, the FDA approved GO graded doses for the treatment of AML.
In addition, other ADC drugs targeting CD33 are also under evaluation.
For example, vadastuximab-Taririne ( VT, SGN-CD33A ) is being studied in a phase 1 trial to evaluate the safety and activity of the drug in combination with HMAs in previously untreated AML.
CD123
Vibecotamab ( XmAb14045 ), a CD123XCD3 BiTEs, is undergoing a phase I study ( NCT02730312 ) in patients with R/R AML, showing antileukemic activity with a CR/CRi ratio of 23%, with CRS being the most common ≥3 The AE.
IMGN632, an ADC targeting CD123, is in Phase I/II study in patients with /R AML ( NCT03386513 ).
Previous results have shown that 33% of patients had objective responses, including 1 case of CR and 3 cases of Cri, without any treatment-related adverse events or deaths.
A different strategy to target CD123 also includes tagraxofusp ( SL-401 ), a fusion protein consisting of IL-3 linked to a truncated diphtheria toxin that inactivates protein synthesis.
In a Phase 1 trial ( NCT03113643 ) evaluating tagraxofusp in combination with AZA or AZA/venetoclax in AML, preliminary results showed favorable responses ( 5/9 CR, 3/9 CRi ).
CD45
Iomab-B, an anti-CD45 antibody conjugated to 131I, was studied in a Phase I clinical trial ( NCT00008177 ) in R/R AML patients with low intensity modulation ( RIC ) with fludarabine ( FLU ) ) program and the combined application of total body irradiation ( TBI ) program.
This study demonstrates that Iomab-B can be safely used in combination with RIC regimens to achieve complete remission in elderly HR AML patients and is currently being tested in the phase III SIERRA trial ( NCT02665065 ).
CD70
Cusatuzumab ( ARGX-110 ) is an anti-CD70 monoclonal antibody.
Based on preclinical results, a phase I/II trial ( NCT03030612 ) evaluated a single dose of cusatuzumab in combination with AZA in elderly patients with untreated AML.
AZA induces CD70 expression on LSCs and thus favors killing in vitro when combined with cusatuzumab.
Ten patients ( 83% ) achieved CR/Cri, 4 patients achieved MRD negativity by flow cytometry, and no dose-limiting toxicities were reported.
Targeted immunotherapy for MDS
Various immunotherapy-based clinical trials are currently underway in previously untreated R/R, HR, and low-risk ( LR ) MDS.
CD47
Magrolimab is one of the most innovative drugs in the treatment of MDS.
An ongoing Phase Ib study ( NCT03248479 ) reported encouraging results of Magrolimab in combination with Aza in patients with MDS.
Overall ORR was 91%, including 42% CR, 24% bone marrow CR (half of which were also accompanied by hematologic improvement), 21% hematologic improvement, and 3% PR.
Immune checkpoint
An ongoing phase II study ( NCT02530463 ) is analyzing the efficacy of ipilimumab and/or nivolumab in MDS.
The results showed that in the HMA failure cohort, the ORR was 36% ( 9%CR, 9%CR/Cri, 18%HI ), and the median OS and PFS were 11.4 and 7.1 months, respectively.
For the first-line cohort, ORR was 67% ( 33% CR and 33% HI ), with median OS and PFS of 12 and 10 months, respectively. Grade ≥3 adverse events included infections in 55%, neutropenia in 46%, rash in 24%, and elevated transaminases in 24%.
These results suggest that further studies with larger cohorts and longer follow-up times are needed.
The TIM-3 inhibitory antibody sabatolimab is in a phase Ib clinical trial ( NCT03066648 ).
The results showed that its safety was similar to that of HMA monotherapy, with an ORR of 56.9%, an mDOR of 16.1 months, and a CR of 21.5 months; the 12-month PFS rate was 51.9%. Notably, patients with adverse risk genotypes ( including TP53 mutations ) responded better than the average response observed in the entire population: ORR was 71.4% and mDOR was 12.6 months.
Currently, other multi-arm Phase II and Phase III studies are ongoing ( NCT03066648 ).
TLR-2
Early Results from Two Phase I/II Trials ( NCT02363491 and NCT03337451 ) Show Favorable Safety Profile of Fully Human IgG4 Monoclonal Antibody Against TLR2 ( OPN-305 ) in Patients With HMA Failure and Transfusion-Dependent LR MDS sex and effectiveness.
No significant toxicity was reported, the ORR was 50%, and 27% of the patients could not require blood transfusion.
CD33
A recent study analyzed anti-CD33 bi- and trispecific antibodies ( TriKEs ) in MDS. AMV564, a CD33XCD3 BiTE, was evaluated in preclinical studies and showed the ability to reduce MDSCs and increase anti-PD-1 antibody activity in vitro.
GTB-3550 is a CD33/CD16/IL15 TriKEs, a Phase I/II trial ( NCT03214666 ) investigating the safety of GTB-3550 in HR-MDS patients showed no significant toxicity while reporting NK in all patients activity increased.
CD123
Recent clinical trials evaluating CD123-targeted therapies have shown positive safety and efficacy. A BiTE of CD123XCD3 ( APVO436 ) is in a phase Ib trial ( NCT03647800 ).
Results No serious adverse events were reported, and 50% achieved mCR. tagraxofusp is in an ongoing phase Ib study ( NCT03113643 ), demonstrating the safety of tagraxofusp + AZA, with the most common ≥3 AEs including anemia, thrombocytopenia, and neutropenia.
Half of the patients achieved CR and 25% mCR; notably, they all had TP53 mutations.
AFM28 is a novel bispecific natural cell engager targeting CD123 on MDS cells and CD16a on NK cells, which has higher stability compared with traditional Fc-optimized IgG1 antibodies and is currently in preclinical research .
Summary
Currently, only a small number of AML patients achieve long-term survival with approved standard treatments.
Outcomes in AML are particularly dismal in older patients who are not candidates for allogeneic hematopoietic stem cell transplantation , for which HMA plus venetoclax is the only available treatment.
In this context, the development of novel immunotherapeutic strategies of monoclonal antibodies against different surface molecules alone or in combination with HMA and possibly BCL2 inhibitors may provide substantial clinical benefit to patients.
The integration of multiple immunotherapeutic strategies in the treatment of AML and MDS still requires large randomized clinical trials to evaluate the true benefit and safety of these new agents.
Furthermore, ongoing studies should also aim at identifying predictive biomarkers of response to specific antibody drug treatments, considering a precision medicine approach to immunotherapy in AML and MDS.
This, in turn, will provide biologically plausible options for specific immunotherapy strategies for individual patients with AML or MDS.
references:
1. New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes. Int J Mol Sci. 2022 Jul; 23(14): 7542.
Antibody Targeted Therapy for Acute myeloid leukemia ( AML ) and myelodysplastic syndrome ( MDS )
(source:internet, reference only)
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