Progress in the treatment of acute myeloid leukemia with antibody drugs

The remission of acute myeloid leukemia (AML) is often not long-lasting after treatment, and traditional treatment methods may be highly toxic
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In recent years, some promising new therapies have emerged
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Antibody-based therapies, such as antibody-drug conjugates (ADC), bispecific T cell adapters (BiTE), and dual affinity retargeting antibodies (DART), and other targeted immunotherapies can target leukemia cells through various mechanisms
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These molecules bind to the antigen target binding domain of antibodies, and by participating in and activating the human immune system to combat leukemia cells expressing the target
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This article mainly introduces the research progress of ADC and bispecific antibodies for the treatment of AML for the reference of readers
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01 Antibody-drug conjugate (ADC) ADC refers to a new type of biopharmaceutical that covalently couples highly selective antibodies and cytotoxic drugs through a linking chain
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Antibodies in ADC can bind to specific antigens on the surface of tumor cells, triggering a biochemical cascade reaction inside tumor cells, resulting in ADC drugs being absorbed into tumor cells, and then using the cytotoxic drugs in ADC to exert tumor-killing effects
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ADC combines the advantages of monoclonal antibody targeting and cytotoxic drugs, greatly reducing the toxic and side effects of anti-tumor drugs through targeting, and provides a wider therapeutic window compared with other chemotherapeutic drugs
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Gemtuzumab Ozogamicin (GO) is a humanized anti-CD33 monoclonal ADC coupled with Calicheamicin.
It is currently the only antibody therapy approved for AML
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The FDA has approved GO for the treatment of elderly relapsed/refractory patients.
However, in the phase III randomized clinical trial of GO combined with induction chemotherapy, the incidence and mortality of patients with sinus obstructive syndrome (SOS) increased, leading to the withdrawal of the drug City
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However, the FDA re-approved the drug for marketing in 2017 because multiple studies have shown that GO as a single-drug therapy and a combination of divided doses (3mg/m2 or 6mg/m2) has a good effect
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A variety of ADC drugs for the treatment of AML are currently under research and development
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These drugs target a variety of cell surface receptors in myeloid malignancies, including CD33, CD123, CD45, and FLT3
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In recent years, the rapid progress in clinical trial research is the ADC targeting CD33 and CD123
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For example, the ADC drug vadastuximab talirine that targets CD33 has shown a higher remission rate in the treatment of patients with relapsed/refractory AML, and the combination of desmethyl drugs (HMA) has achieved about 70% of untreated patients.
CR/CRi rate, including minimal residual disease (MRD) negative remission rate is also higher
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Unfortunately, a subsequent placebo-controlled phase III randomized clinical trial comparing HMA and combination therapy was aborted due to an increase in patient mortality.
The increase in patient mortality may be related to the bone marrow suppression of ADC
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Another ADC under clinical research is IMGN632, which targets CD123
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In early clinical trials, the drug showed good tolerability.
Most of the relapsed/refractory patients who received treatment have reduced bone marrow blasts, and most of them have obtained CR/CRi
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02 Bispecific antibodies Bispecific antibodies also have considerable prospects in the treatment of AML
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BiTE usually consists of two single-chain variable fragments derived from natural antibodies.
These fragments target both tumor antigens and CD3-expressing T cells
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In this way, BiTE can re-target and activate the T cell-mediated immune system to fight tumor cells and produce clinical remission
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DART also activates the immune system of treated patients by retargeting T cells
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However, in contrast to BiTE, DART molecules carry two specific variable domains in alternating order on both chains
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Currently, research on bispecific antibody drugs targeting multiple antigens on AML cells is underway
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The research results of the DART drug flotetuzumab targeting CD123 as a rescue treatment for patients with relapsed/refractory AML show that this drug has a high single-drug compound remission rate, and can be used in early relapses or primary refractory diseases (especially in In the adverse risk group), the compound response rate is close to 30%, and the median overall survival is about 10 months
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Other bispecific antibodies under clinical research include drugs targeting CD33, FLT3 and WT1
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Although some side effects (severe cytokine release syndrome or nervous system toxicity) have been observed for these drugs, this treatment method still shows good clinical application prospects
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03 Summary In the past five years, the treatment of AML has progressed rapidly
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In clinical trials, bispecific antibodies and ADCs targeting multiple antigens on the surface of AML cells have shown significant therapeutic effects
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In the next ten years, it is hoped that some of these promising drugs will be approved for the treatment of AML like GO
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Reference source: Amir T.
Fathi.
2021 SOHO.
EXABS-178-AML.
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