Did you mean: xentuzumab
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American Society of Clinical Oncology... 2014Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the... (Review)
Review
Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 ((213)Bi)-labeled lintuzumab. In a subsequent study, (213)Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of (213)Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 ((225)Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that (225)Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose (225)Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using (213)Bi- and astatine-211 ((211)At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios.
Topics: Alpha Particles; Animals; Antibodies, Monoclonal, Humanized; Bismuth; Clinical Trials as Topic; Humans; Immunoconjugates; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Radioimmunotherapy; Radioisotopes
PubMed: 24857092
DOI: 10.14694/EdBook_AM.2014.34.e126 -
Molecules (Basel, Switzerland) Oct 2022Positron emission tomography (PET) imaging is a powerful non-invasive method to determine the in vivo behavior of biomolecules. Determining biodistribution and...
Positron emission tomography (PET) imaging is a powerful non-invasive method to determine the in vivo behavior of biomolecules. Determining biodistribution and pharmacokinetic (PK) properties of targeted therapeutics can enable a better understanding of in vivo drug mechanisms such as tumor uptake, off target accumulation and clearance. Zirconium-89 (Zr) is a readily available tetravalent PET-enabling radiometal that has been used to evaluate the biodistribution and PK of monoclonal antibodies. In the current study, we performed in vitro and in vivo characterization of Zr-lintuzumab, a radiolabeled anti-CD33 antibody, as a model to evaluate the in vivo binding properties in preclinical models of AML. 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 biological activity of Zr-lintuzumab was evaluated in a panel of CD33 positive cells using flow cytometry. Fox Chase SCID mice were injected with 2 × 10 OCI-AML3 cells into the right flank. After 12 days, a cohort of mice ( = 4) were injected with Zr-lintuzumab via tail vein. PET/CT scans of mice were acquired on days 1, 2, 3 and 7 post Zr-lintuzumab injection. To demonstrate Zr-lintuzumab specific binding to CD33 expressing tumors in vivo, a blocking study was performed. This cohort of mice ( = 4) was injected with native lintuzumab and 24 h later Zr-lintuzumab was administered. This group was imaged 3 and 7 days after injection of Zr-lintuzumab. A full ex vivo biodistribution study on both cohorts was performed on day 7. The results from the PET image and ex vivo biodistribution studies were compared. Lintuzumab was successfully radiolabeled with Zr resulting in a 99% radiochemical yield. The Zr-lintuzumab radioconjugate specifically binds CD33 positive cells in a similar manner to native lintuzumab as observed by flow cytometry. PET imaging revealed high accumulation of Zr-lintuzumab in OCI-AML3 tumors within 24h post-injection of the radioconjugate. The Zr-lintuzumab high tumor uptake remains for up to 7 days. Tumor analysis of the PET data using volume of interest (VOI) showed significant blocking of Zr-lintuzumab in the group pre-treated with native lintuzumab (pre-blocked group), thus indicating specific targeting of CD33 on OCI-AML3 cells in vivo. The tumor uptake findings from the PET imaging study are in agreement with those from the ex vivo biodistribution results. PET imaging of Zr-lintuzumab shows high specific uptake in CD33 positive human OCI-AML3 tumors. 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.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Deferoxamine; Humans; Mice; Mice, SCID; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Tissue Distribution; Zirconium
PubMed: 36235126
DOI: 10.3390/molecules27196589 -
Clinical Cancer Research : An Official... May 2022The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a...
PURPOSE
The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a radionuclide yielding 4 α-particles. This first-in-human, phase I trial was conducted to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab.
PATIENTS AND METHODS
Eighteen patients (median age, 64 years; range, 45-80) with relapsed or refractory AML received a single infusion of 225Ac-lintuzumab at activities of 18.5 to 148 kBq/kg.
RESULTS
The maximum tolerated dose was 111 kBq/kg. Dose-limiting toxicities included myelosuppression lasting > 35 days in one patient receiving 148 kBq/kg and death from sepsis in two patients treated with 111 and 148 kBq/kg. Myelosuppression was the most common toxicity. Significant extramedullary toxicities were limited to transient grade 3 liver function abnormalities. Pharmacokinetics were determined by gamma counting serial whole blood, plasma, and urine samples at energy windows for the 225Ac daughters, francium-221 and bismuth-213. Two-phase elimination kinetics were seen with mean plasma t1/2 - α and t1/2 - β of 1.9 and 38 hours, respectively. Peripheral blood blasts were eliminated in 10 of 16 evaluable patients (63%) but only at doses of ≥ 37 kBq/kg. Bone marrow blasts were reduced in 10 of 15 evaluable patients (67%), including 3 patients with marrow blasts ≤ 5% and one patient with a morphologic leukemia-free state.
CONCLUSIONS
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.
Topics: Actinium; Alpha Particles; Antibodies, Monoclonal, Humanized; Humans; Immunoconjugates; Leukemia, Myeloid, Acute; Middle Aged
PubMed: 35247915
DOI: 10.1158/1078-0432.CCR-21-3712 -
Journal For Immunotherapy of Cancer Sep 2021Successful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly...
BACKGROUND
Successful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial experiences with CD19 CAR T cell immunotherapy for patients with B-cell malignancies highlighted the critical impact of intracellular costimulatory domain selection (CD28 vs 4-1BB (CD137)) on CAR T cell expansion and in vivo persistence that may impact clinical outcomes. However, the impact of costimulatory domains on the efficacy of myeloid antigen-directed CAR T cell immunotherapy remains unknown.
METHODS
In this preclinical study, we developed six CAR constructs targeting CD33, a highly expressed and validated AML target, comprised of one of three single-chain variable fragments with CD3ζ and either CD28 or 4-1BB costimulatory domains. We systematically compared the preclinical in vitro and in vivo efficacy of T cells lentivirally transduced with CD33 CAR constructs (CD33CARTs) against human AML.
RESULTS
We observed potent in vitro cytokine production and cytotoxicity of CD33CARTs incubated with human CD33+ AML cell lines, as well as robust in vivo antileukemia activity in cell line and childhood AML patient-derived xenograft (PDX) models. Gemtuzumab-based CD33CARTs were unexpectedly toxic in vivo in animal models despite observed in vitro anti-leukemia activity. CD28-based CD33CARTs consistently induced more robust inhibition of leukemia proliferation in AML cell line and PDX models than did 4-1BB-based CD33CARTs. A 'best-in-class' lintuzumab-CD28/CD3ζ CAR construct was thus selected for clinical translation.
CONCLUSIONS
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.
TRIAL REGISTRATION NUMBER
clinicaltrials.gov; NCT03971799.
Topics: Animals; Female; Humans; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Male; Mice; Receptors, Chimeric Antigen; Sialic Acid Binding Ig-like Lectin 3; T-Lymphocytes
PubMed: 34531250
DOI: 10.1136/jitc-2021-003149 -
Experimental Hematology Jul 2008Since the approval of rituximab in 1997, monoclonal antibodies have come to play an important role in the therapy of hematological malignancies. Rituximab, gemtuzumab... (Review)
Review
Since the approval of rituximab in 1997, monoclonal antibodies have come to play an important role in the therapy of hematological malignancies. Rituximab, gemtuzumab ozogamicin, and alemtuzumab are US Food and Drug Administration-approved for treatment of B-cell lymphomas, acute myeloid leukemia, and chronic lymphocytic leukemia, respectively. Multiple monoclonal antibodies directed against new and not-so-new cellular antigens are undergoing development and investigation all over the world. Most of these new compounds have undergone primatization or humanization, improving their specificity and decreasing their antigenicity when compared to earlier murine or chimeric products. This review will focus on three major aspects of monoclonal antibody therapy: 1) new therapeutic approaches with currently approved agents; 2) preclinical and clinical experience accumulated on new agents in the last few years; discussion will include available phase I, II, and III data on ofatumumab, epratuzumab, CMC-544, HeFi-1, SGN-30, MDX-060, HuM195 (lintuzumab), galiximab, lumiliximab, zanolimumab, and apolizumab; and 3) the role of naked and radiolabeled monoclonal antibodies in the hematopoietic stem cell transplantation setting.
Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Antigens, Neoplasm; Antineoplastic Agents; Clinical Trials as Topic; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Mice; United States; United States Food and Drug Administration
PubMed: 18565392
DOI: 10.1016/j.exphem.2008.04.018 -
Journal of Nuclear Medicine Technology Mar 2022For CE credit, you can access the test for this article, as well as additional CE tests, online at https://www.snmmilearningcenter.org Complete the test online no...
For CE credit, you can access the test for this article, as well as additional CE tests, online at https://www.snmmilearningcenter.org Complete the test online no later than March 2025. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 75% of the questions correctly to receive Continuing Education Hour (CEH) credit. Credit amounts can be found in the SNMMI Learning Center Activity. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test.α-emitting radionuclides provide an effective means of delivering large radiation doses to targeted treatment locations. RaCl is Food and Drug Administration-approved for treatment of metastatic castration-resistant prostate cancer, and Ac (Ac-lintuzumab) radiolabeled antibodies have been shown to be beneficial for patients with acute myeloid leukemia. In recent years, there has been increasing use of α-emitters in theranostic agents with both small- and large-molecule constructs. The proper precautionary means for their use and surveying documentation of these isotopes in a clinical setting are an essential accompaniment to these treatments. Patient treatment data collected over a 3-y period, as well as regulatory requirements and safety practices, are described. Commonly used radiation instruments were evaluated for their ability to identify potential radioactive material spills and contamination events during a clinical administration of Ac. These instruments were placed at 0.32 cm from a 1.0-cm Ac disk source for measurement purposes. Radiation background values, efficiencies, and minimal detectable activities were measured and calculated for each type of detector. The median external measured dose rate from RaCl patients ( = 611) was 2.5 μSv h on contact and 0.2 μSv h at 1 m immediately after administration. Similarly, Ac-lintuzumab ( = 19) patients had median external dose rates of 2.0 μSv h on contact and 0.3 μSv h at 1 m. For the measurement of Ac samples, a liquid scintillation counter was found to have the highest overall efficiency (97%), whereas a ZnS α-probe offered the lowest minimal detectable activity at 3 counts per minute. In this article, we report data from 630 patients who were undergoing treatment with the α-emitting isotopes Ra and Ac. Although α-emitters have the ability to deliver a higher internal radiation dose to the exposed tissues than can other unsealed radionuclides, they typically present minimal concerns about external dose rate. Additionally, α-radiation can be efficiently detected with appropriate radiation instrumentation, such as a liquid scintillation counter or ZnS probe, which should be prioritized when surveying for spills of α-emitters.
Topics: Humans; Male; Prostatic Neoplasms; Radioisotopes
PubMed: 34750237
DOI: 10.2967/jnmt.121.262294 -
Cancer Medicine Feb 2021Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new...
PURPOSE
Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low-dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. Actinium-lintuzumab ( Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single-agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer.
EXPERIMENTAL DESIGN
Here we investigated the potential for Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML.
RESULTS
We demonstrated that Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models.
CONCLUSIONS
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.
Topics: Actinium; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Myeloid, Acute; Mice; Mice, SCID; Proto-Oncogene Proteins c-bcl-2; Sialic Acid Binding Ig-like Lectin 3; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33347715
DOI: 10.1002/cam4.3665 -
Clinical Cancer Research : An Official... Nov 2010Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To...
PURPOSE
Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle-emitting radionuclide bismuth-213 ((213)Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of (213)Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy.
EXPERIMENTAL DESIGN
Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m(2)/d) for 5 days followed by (213)Bi-lintuzumab (18.5-46.25 MBq/kg).
RESULTS
The MTD of (213)Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment-related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by (213)Bi-lintuzumab was achieved after partial cytoreduction with cytarabine.
CONCLUSIONS
Sequential administration of cytarabine and (213)Bi-lintuzumab is tolerable and can produce remissions in patients with AML.
Topics: Adult; Aged; Aged, 80 and over; Alpha Particles; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Bismuth; Cytarabine; Drug Administration Schedule; Female; Humans; Immunoconjugates; Leukemia, Myeloid, Acute; Male; Middle Aged; Radioimmunotherapy; Radioisotopes; Remission Induction
PubMed: 20858843
DOI: 10.1158/1078-0432.CCR-10-0382 -
Haematologica Jan 2013Improving outcomes in older adults with acute myeloid leukemia remains a formidable challenge. Lintuzumab (SGN-33; HuM195) is a humanized monoclonal antibody directed... (Comparative Study)
Comparative Study Randomized Controlled Trial
Improving outcomes in older adults with acute myeloid leukemia remains a formidable challenge. Lintuzumab (SGN-33; HuM195) is a humanized monoclonal antibody directed against CD33, which is expressed on the majority of myeloblasts in acute myeloid leukemia. The primary objective of this randomized, double-blinded, placebo-controlled trial was to determine whether addition of lintuzumab to low-dose cytarabine would increase overall survival in adults aged 60 years and over with untreated acute myeloid leukemia. Randomization was stratified by age, previous hematologic disorder, and performance status. All patients received cytarabine (20 mg subcutaneously twice daily) on Days 1-10 of each 28-day cycle. Patients received lintuzumab (600 mg) or placebo intravenously once weekly in Cycle 1 and once every other week in Cycles 2-12. A total of 211 patients (107 lintuzumab, 104 placebo) were randomized. Median age was 70 years (range 60-90). Survival was not significantly prolonged with lintuzumab treatment (hazard ratio 0.96; 95% confidence interval (CI) 0.72-1.28; P=0.7585). Median survival was similar between treatment arms (4.7 months lintuzumab vs. 5.1 months placebo) and in the subgroup of patients with high-risk cytogenetics (4.5 months). Infusion-related reactions, predominantly Grades 1-2, occurred more commonly in the lintuzumab arm (51% vs. 7% placebo); no other clinically significant difference in safety was noted. These results confirm that lintuzumab in combination with low-dose cytarabine did not prolong survival and that low-dose cytarabine remains a valid comparator for trials of non-intensive therapies in older patients with acute myeloid leukemia, regardless of cytogenetic profile.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Double-Blind Method; Female; Humans; Internationality; Leukemia, Myeloid, Acute; Male; Middle Aged; Survival Rate; Treatment Outcome
PubMed: 22801961
DOI: 10.3324/haematol.2012.066613 -
MAbs 2009Despite therapeutic advances, the long-term survival rates for acute myeloid leukemia (AML) are estimated to be 10% or less, pointing to the need for better treatment...
Despite therapeutic advances, the long-term survival rates for acute myeloid leukemia (AML) are estimated to be 10% or less, pointing to the need for better treatment options. AML cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Thus, the in vitro and in vivo anti-tumor activities of lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, were investigated. In vitro assays were used to assess the ability of lintuzumab to mediate effector functions and to decrease the production of growth factors from AML cells. SCID mice models of disseminated AML with the multi-drug resistance (MDR)-negative HL60 and the MDR(+), HEL9217 and TF1-alpha, cell lines were developed and applied to examine the in vivo antitumor activity. In vitro, lintuzumab significantly reduced the production of TNFalpha-induced pro-inflammatory cytokines and chemokines by AML cells. Lintuzumab promoted tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities against MDR(-) and MDR(+) AML cell lines and primary AML patient samples. At doses from 3 to 30 mg/kg, lintuzumab significantly enhanced survival and reduced tumor burden in vivo, regardless of MDR status. Survival of the mice was dependent upon the activity of resident macrophages and neutrophils. The results suggest that lintuzumab may exert its therapeutic effects by modulating the cytokine milieu in the tumor microenvironment and through effector mediated cell killing. Given that lintuzumab induced meaningful responses in a phase 1 clinical trial, the preclinical antitumor activities defined in this study may underlie its observed therapeutic efficacy in AML patients.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Disease Models, Animal; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Mice; Mice, SCID; Phagocytosis; Sialic Acid Binding Ig-like Lectin 3; Treatment Outcome; U937 Cells
PubMed: 20065652
DOI: 10.4161/mabs.1.5.9288