DTX33 Antibody
Description
CD33 as a Therapeutic Target in Acute Myeloid Leukemia (AML)
CD33 is a transmembrane glycoprotein expressed on myeloid cells and >85% of AML blasts . Its role in AML makes it a prime target for immunotherapies, including monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies.
| Therapeutic Approach | Mechanism | Examples |
|---|---|---|
| Monoclonal Antibodies | ADCC, CDC, or direct cytotoxicity | Gemtuzumab ozogamicin (ADC), Vadastuximab talirine (ADC), Lintuzumab (mAb) |
| CAR T-Cell Therapy | Redirected T-cell cytotoxicity | CD33CARTs with 4-1BB/CD3ζ or CD28/CD3ζ endodomains |
| Radiolabeled Antibodies | Targeted radiation delivery | ¹³¹I-p67 (anti-CD33) |
Mechanisms of Action: CD33 Antibodies
CD33 antibodies exert antitumor effects through:
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Antibody-Dependent Cellular Cytotoxicity (ADCC): NK cells lyse CD33+ AML cells via Fc receptor engagement .
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Complement-Dependent Cytotoxicity (CDC): Activation of the complement system to induce cell lysis .
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Targeted Drug Delivery: ADCs (e.g., gemtuzumab ozogamicin) release cytotoxic payloads upon internalization .
Key Preclinical Findings:
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Fc-engineered CD33mAbs (e.g., Vadastuximab) enhance NK cell-mediated lysis of AML blasts, even after decitabine pretreatment .
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CD33CARTs with CD28 costimulatory domains show superior cytotoxicity in AML PDX models compared to 4-1BB-based constructs .
Clinical Applications of CD33 Antibodies
Radiolabeled Anti-CD33 Antibodies
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¹³¹I-p67: A phase I trial demonstrated feasibility in delivering targeted radiation to marrow, with three of four patients achieving remission .
Patient Dose (mCi) Outcome UPN1 110–330 Alive (195–477 days) UPN2 110–330 Alive (195–477 days) UPN3 110–330 Alive (195–477 days) UPN4 110–330 Died (day 111)
CAR T-Cell Therapy
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CD33CARTs: In AML PDX models, lintuzumab-based CD28/CD3ζ CAR T-cells reduced tumor burden more effectively than gemtuzumab-based constructs .
Integration with Chemotherapy: DTX and Beyond
While "DTX33 Antibody" is not explicitly described, studies highlight synergies between DTX (Docetaxel) and immunotherapy:
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Metronomic DTX: Low-dose, frequent administration enhances antigen presentation (via PI3K/Akt/NF-κB signaling) and synergizes with anti-PD-1/PD-L1 mAbs .
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Biodistribution: Polymer micelles (e.g., MPEG-PDLLA-PLL) improve DTX delivery to tumors, reducing off-target toxicity .
Challenges and Limitations
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Antigen Density: CD33 expression varies across AML subtypes, impacting CAR T-cell efficacy .
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Toxicity: Gemtuzumab ozogamicin and Vadastuximab talirine are associated with hepatotoxicity and thrombocytopenia .
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Resistance: CD33 downregulation or splice variants (e.g., rs12459419 polymorphism) may limit response .
Future Directions
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Novel CAR Constructs: Testing bispecific CARs (e.g., CD33/CD123) to overcome antigen heterogeneity.
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Combination Therapies: Pairing CD33CARTs with checkpoint inhibitors or metronomic chemotherapy.
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Biomarker-Guided Therapy: Stratifying patients based on CD33 site density or genetic polymorphisms.
