Zamyl (lintuzumab) / Pfizer - LARVOL DELTA

A logic-gated chimeric antigen receptor T cell (CAR T) for post-transplant acute myeloid leukemia (AML) that distinguishes donor and recipient hematopoiesis (AACR 2025) - P1/2 | "We have developed a cell therapy strategy to leverage HLA mismatched stem cell transplants using a Tmod HLA-A*02 blocker. This approach could be applied to patients who have relapsed after a mismatched transplant or integrated into a stem cell transplant to prevent relapse. Pre-clinical data of this design demonstrates selectivity between HLA-A*02 positive and HLA-A*02 negative cells, and dual antigen activity addresses antigen escape."

CAR T-Cell Therapy • Post-transplantation • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CD33 • HLA-A

Targeting the Membrane-Proximal Domain of CD33 to Maximize the Efficacy of Natural Killer Cell-Based Immunotherapies (ASH 2024) - "Background : Improved survival of some patients with AML with the antibody-drug conjugate gemtuzumab ozogamicin (GO) validates CD33 as a therapeutic target, but GO is often ineffective...Our studies are also the first to show an advantage of targeting CD33 membrane-proximally to enhance CAR-NK efficacy. Together, our findings support the further development of CD33C2-set-directed NK cell-based therapies for AML and other CD33-expressing neoplasms."

Clinical • Hematological Malignancies • Leukemia • Oncology • CD33 • FCGR3A • IFNG • TNFA

89Zr-immunoPET-guided selection of a CD33xIL15 fusion protein optimized for antitumor immune cell activation and in vivo tumour retention in acute myeloid leukaemia. (PubMed, Eur J Nucl Med Mol Imaging) - "This work demonstrates that CD33xIL15 fusion proteins are capable of targeting leukemic cells and stimulating local T cells in vitro and of concentrating in the tumour in AML xenografts. It also highlights the importance of 89Zr-immunoPET to guide the development and selection of tumour-targeted antibody-cytokine fusion proteins."

Immune cell • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD33 • IL15

Developing a membrane-proximal CD33-targeting CAR T cell. (PubMed, J Immunother Cancer) - "Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models."

CAR T-Cell Therapy • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33

Targeting CD33+ acute myeloid leukemia with GLK-33, a lintuzumab-auristatin conjugate with a wide therapeutic window. (PubMed, Mol Cancer Ther) - "While previous CD33-targeting antibody-drug conjugates (ADCs) like gemtuzumab ozogamicin (GO, Mylotarg) have shown efficacy in AML treatment, they have suffered from toxicity and narrow therapeutic window...The development of GLK-33 addresses the limitations of previous ADCs, offering a wider therapeutic window, improved tolerability, and activity against drug-resistant leukemia cells. These findings encourage further exploration of GLK-33 in AML through clinical trials."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33

HuM195 and its single-chain variable fragment increase Aβ phagocytosis in microglia via elimination of CD33 inhibitory signaling. (PubMed, Mol Psychiatry) - "Importantly, recombinant IL33 potentiates the uptake of Aβ42 in monocytes. Collectively, our findings provide unanticipated mechanistic insight into the role of CD33 signaling in both monocytes and microglia and define a molecular basis for the development of CD33-based therapy of AD."

Journal • Alzheimer's Disease • CNS Disorders • Aβ42 • CD33 • IL33

Trial in Progress: Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients with Relapsed or Refractory Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation (TCT-ASTCT-CIBMTR 2024) - P1/2 | "Lymphodepletion with fludarabine (total 120 mg/m2) and cyclophosphamide (total 1000 mg/m2) will be given prior to VCAR33 infusion...Follow up on study will continue for up to 2 years after infusion. Patients may undergo second alloHCT for consolidation of remission or for rescue of prolonged cytopenia due to on-target off-tumor effects of VCAR33."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation • CD33

Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients with Relapsed or Refractory Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation (ASH 2023) - "CD33 is a preferential target for AML CAR T cell therapy as it is expressed on the majority (>80%) of AML blasts and because prior clinical experience with gemtuzumab ozogamicin (GO; tradename: MylotargTM) has demonstrated the safety and efficacy of targeting CD33...Patients will receive lymphodepletion on days -5 to -2 with fludarabine (total 120 mg/m2) and cyclophosphamide (total 1000 mg/m2) followed by infusion of VCAR33 on Day 0...*NCT number pending. Clinical trial information submitted to CT.gov on July 19, 2023."

Clinical • P1/2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation • CD33

Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16/NKG2D Immune Modulating TriNKET® BMS-986357 (CC-96191) (ASH 2023) - P1 | "CD33 is widely expressed by myeloid cells and is a validated drug target in acute myeloid leukemia (AML), as shown by the benefit of some patients from the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO)...In summary, our findings demonstrate that BMS-986357 TriNKET® has potent CD33-dependent cytolytic activity in vitro against human AML cells, supporting the drug's exploration in early phase clinical trials. One such trial (NCT04789655) has opened accrual for adults with relapsed/refractory AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • CSF2 • FCGR3A • IFNG • IL6 • NKG2D

An MHC class II targeted immunotherapy for CD33-positive pediatric acute myeloid leukemia (SITC 2023) - "CD33-M2T has demonstrated clear advantages over anti-CD33 monoclonal antibodies (e. g. , gemtuzumab, lintuzumab), including the ability to bind to the truncated alternatively spliced version of CD33, long duration of action, and no overt toxicities in mice. Conclusions These experiments demonstrate the preclinical potential of an innovative immunotherapy targeting CD33-positive childhood AML."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33

Targeting myeloid-derived suppressor cells with actinium-225 lintuzumab, a CD33 antibody radioconjugate to enhance antitumor immunity (AACR 2023) - "In this study, we demonstrate CD33 ARC alpha targeted radiotherapy depletes human CD33 positive immune suppressing MDSCs present in multiple cancer types, to enhance antitumor immunity. These findings present a translatable strategy that supports further evaluation of 225Ac lintuzumab as a MDSC targeting agent to improve the efficacy of antitumor therapies."

Myeloid-derived suppressor cells • Acute Myelogenous Leukemia • Oncology • CD33 • CD34

CD33 SNP Genotype and Splice Variation Are Associated with CD33 Cell Surface Expression and SGN-CD33A Pharmacokinetics (ASH 2018) - P1, P3; "...Expression of CD33 is in part mediated by splicing of the CD33 transcript, and has been demonstrated to be one of the factors that may mediate response to the ADC gemtuzumab ozogamicin, which results in significant benefit in some patients but lacks responses in others...We analyzed CD33 genotype variation in bone marrow (BM) or peripheral blood (PB) samples from patients treated with SGN-33A as either monotherapy (NCT01902329; n=133) or in combination with hypomethylating agents (HMAs; NCT02785900; n=83)...We show that CD33 SNP genotype is associated with CD33 expression, with CC patients demonstrating higher CD33 as detected by flow cytometry; and that CD33 SNP genotype affects the PK profile of SGN-CD33A, with TT patients having higher levels of drug exposure. Our findings suggest that the CD33 genotype can impact CD33 expression, PK profile, and trafficking of bound agents and thus may impact therapeutic targeting of CD33-directed agents."

IO biomarker • PK/PD data • Acute Myelogenous Leukemia • Biosimilar

"Sameem Abedin presenting on Lintuzumab - great study! @MedicalCollege #ASH22" (@lauracmichaelis)

In Vitro and In Vivo Characterization of Zirconium-Labeled Lintuzumab Molecule. (PubMed, Molecules) - " Lintuzumab was conjugated to p-SCN-Bn-deferoxamine (DFO) and labeled with Zr using a 5:1 µCi:µg specific activity at 37 °C for 1h...The results from the image study agree with the observations from the ex vivo biodistribution study. Our findings collectively suggest that PET imaging using Zr-lintuzumab could be a powerful drug development tool to evaluate binding properties of anti-CD33 monoclonal antibodies in preclinical cancer models."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Beyond gemtuzumab ozogamicin: A systematic review of antibody therapies for acute myeloid leukemia. (ASCO 2022) - "gave a combination of talacotuzumab (anti-CD123 antibody) + decitabine to AML patients and reported an ORR of 27% (42/157) in the talacotuzumab + decitabine arm...studied flotetuzumab (anti-CD3 x anti-CD123 DART) and reported an ORR of 30% (9/30) in patients treated at the recommended phase two dose...noticed a CR in 26% (30/117) of patients who received a combination of vadastuximab talirine (anti-CD33 ADC) with azacytidine/decitabine...reported an ORR of 14% (5/32) in the lirilumab + azacytidine arm...administered nivolumab (anti-PD1 antibody) + azacytidine and noticed an ORR of 33% (23/70)...reported that the durvalumab (anti-PD-L1 antibody) + azacytidine arm had a lower ORR than the control arm (31% vs 35%)... Antibody-based therapies are showing great promise for the treatment of AML but are associated with various adverse effects. More prospective clinical trials are needed to further assess the long-term benefits of such medications.AE: adverse events; GI:..."

Review • Acute Myelogenous Leukemia • Gastrointestinal Disorder • Hematological Malignancies • Inflammation • Leukemia • Oncology • CD123

Where do we stand with radioimmunotherapy for acute myeloid leukemia? (PubMed, Expert Opin Biol Ther) - P3 | "An I-labeled CD45 antibody (Iomab-B [apamistamab-I131]) is currently studied in the registration-type phase 3 SIERRA trial (NCT02665065) for this purpose...Clinical efforts with At-labeled CD45 antibodies and Ac-labeled CD33 antibodies (e.g. Ac-lintuzumab [Actimab-A]) are ongoing. A first anti-AML RIT may soon become available. This might propel further work to develop RIT-based treatments for AML, with many such efforts already ongoing."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD33 • PTPRC

Treatment of Patients with Acute Myeloid Leukemia with the Targeted Alpha-Particle Nano-Generator Actinium-225-Lintuzumab. (PubMed, Clin Cancer Res) - "Therapy for AML with the targeted α-particle generator 225Ac-lintuzumab was feasible with an acceptable safety profile. Elimination of circulating blasts or reductions in marrow blasts were observed across all dose levels."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Septic Shock

Anti-CD33 actinium-225 targeted radioimmunotherapy enhances the biologic activity of anti-CD47 antibody immunotherapy in preclinical models of acute myeloid leukemia (SITC 2021) - "Background Actimab-A, the anti-CD33 antibody lintuzumab armed with the radioisotope Actinium-225 (Ac-225), has demonstrated single agent antileukemic effects in patients with relapsed or refractory acute myeloid leukemia (AML)...Conclusions Our findings suggest a novel synergistic mechanism whereby the CD33 ARC targeted radiation induces upregulation of CRT, thereby potentiating a pro-phagocytic innate immune response in combination with anti-CD47 blocking antibody. More importantly, clinical translation of this approach could enhance therapeutic efficacy in AML and warrants further preclinical exploration."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CALR

Radiation Safety Considerations and Clinical Advantages of Alpha-Emitting Therapy Radionuclides. (PubMed, J Nucl Med Technol) - "Radium-223 dichloride (RaCl) is FDA approved for treatment of metastatic castration-resistant prostate cancer (mCRPC) and Actinium-225 (Ac-Lintuzumab) radiolabeled antibodies have been shown to be beneficial for patients with acute myeloid leukemia...While alpha emitters have ability to deliver higher internal radiation dose to the tissues exposed as compared with other unsealed radionuclides, they typically present minimal external dose rate concerns. Additionally, alpha radiation can be efficiently detected with appropriate radiation instrumentation, such as a liquid scintillation counter or ZnS probe, that should be prioritized when surveying for spills of alpha-emitters."

Clinical • Journal • Acute Myelogenous Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Oncology • Prostate Cancer • Solid Tumor

Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design. (PubMed, J Immunother Cancer) - P1/2 | "CD33 is a critical antigen for potential immunotherapeutic targeting in patients with AML. Based on this rigorous preclinical evaluation, our validated clinical grade lintuzumab-CD28/CD3ζ CD33CART immunotherapy is now under evaluation in a first-in-child/first-in-human phase 1 clinical trial for children and adolescents/young adults with relapsed/refractory AML."

CAR T-Cell Therapy • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Oncology • Pediatrics • CD19 • CD33 • TNFRSF9

What are the main advances in patient care that we are seeing with novel agents for leukemia? (YouTube) - "During the 2021 ASCO Annual Meeting, the ALL Hub spoke with Jorge Cortes...Cortes begins by outlining two practice-changing trials and their encouraging response rates. The first being the ZUMA-3 (utilizing CAR T-cell therapy), and the second investigating lintuzumab regimes in adult Philadelphia chromosome-positive ALL patients. He goes on to review two further studies investigating inotuzumab and the value of assessing MRD in patients."

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225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. (PubMed, Cancer Med) - P1/2 | "There results suggest that the combination of Ac-lintuzumab with venetoclax is a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML. Clinical trial of this combination therapy (NCT03867682) is currently ongoing."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • MCL1

Targeted Alpha-Particle Therapy for Hematologic Malignancies. (PubMed, J Med Imaging Radiat Sci) - "Studies with Bi-lintuzumab provided proof of principle for systemically administered α-particle therapy. Ac-lintuzumab was active against advanced AML and produced remissions in older patients with untreated AML in combination with low-dose cytarabine and as a single agent. These studies provide the rationale for development of Ac-lintuzumab in combination with a variety of agents in AML and in other hematologic malignancies such as myelodysplastic syndrome and multiple myeloma."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Oncology

Response to induction or hypomethylating agent therapy among patients with myeloproliferative neoplasms progressing to accelerated or leukemic phase. (ASCO 2017) - "...The only HMA response was on a trial of HMA+SGN33a... AML or accelerated phase disease arising out of MPN carries a dismal prognosis. HMA monotherapy had little efficacy in this group (0/7 achieved remission). Allogeneic transplantation offered the best chance of survival at one year, but fewer than a third of patients were able to proceed to transplant."

Retrospective data • Acute Myelogenous Leukemia • Biosimilar • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology • Venous Thromboembolism

Targeted Alpha-Particle Therapy for Hematologic Malignancies. (PubMed, Semin Nucl Med) - "Initial studies showed that Bi-labeled lintuzumab had antileukemic activity and could produce remissions after partial cytoreduction with cytarabine...In a phase II study, treatment with Ac-lintuzumab monotherapy for a similar patient population resulted in remission in 69% of patients receiving two fractions of 74 kBq/kg and 22% of patients receiving two 55.5-kBq/kg fractions. Additionally, TAT may be useful in intensifying antileukemic therapy prior to hematopoietic cell transplantation, and pretargeting strategies offer the possibility for improved tumor-to-normal organ dose ratios."

Journal • Review