Differences in CD33 Intensity Between Various Myeloid Neoplasms

Jilani, Iman; Estey, Elihu; Huh, Yang O.; Joe, Youngson; Manshouri, Taghi; Yared, Marwan; Giles, Francis J.; Kantarjian, Hagop M.; Cortes, Jorge; Thomas, Deborah A.; Keating, Michael J.; Freireich, Emil J.; Albitar, Mäher

doi:10.1309/1wmw-cmxx-4wn4-t55u

Cited by 117 publications

(80 citation statements)

References 22 publications

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“…It is predominantly expressed on myeloidderived cells and found overexpressed on bone marrow cells from patients with AML, chronic myelogenous leukemia, and myelodysplastic syndrome (6). Importantly, CD33 has been found expressed on leukemic stem cells, and only CD33 þ leukemic stem cells gave rise to leukemia in mice (7,8).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

Friedrich

Henn

Raum

et al. 2014

Molecular Cancer Therapeutics

118

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There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell-engaging (BiTE, a registered trademark of Amgen) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3e of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC 50 values ranging between 0.4 pmol/L and 3 pmol/L (18-149 pg/mL) by previously resting, AMG 330-redirected T cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of IFN-g, TNF, interleukin (IL)-2, IL-10, and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of patients with AML did not significantly affect activities of AMG 330. Neoexpression of CD33 on newly activated T cells was negligible as it was limited to 6% of T cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T cells. AMG 330 warrants further development as a potential therapy for AML. Mol Cancer Ther; 13(6); 1549-57. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

Friedrich

Henn

Raum

et al. 2014

Molecular Cancer Therapeutics

118

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“…28 -30 The efficacy of gemtuzumab is associated with the ongoing renewal of cell surface CD33 expression. 2,30 Although we have found no difference to date in the response rates between patients with AML or RAEB/ RAEBT to gemtuzumab -containing regimens, 3,5,6 the issue of whether CD33 expression or metabolism differs in these patient populations is worthy of further study.…”

Section: Discussionmentioning

confidence: 88%

Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high‐risk myelodysplastic syndromes

Tsimberidou

Estey

Cortes

et al. 2003

Cancer

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BACKGROUNDGemtuzumab is used to treat patients with previously untreated or recurrent acute myelogenous leukemia (AML). The fludarabine and cytarabine (ara‐C) regimen is active in these patients. Resistance to gemtuzumab is associated with blast multidrug resistance (MDR). The objectives of this study were to evaluate the efficacy and toxicity of a combination regimen of gemtuzumab, fludarabine, ara‐C, and the MDR modifier (cyclosporine [CyA]) in patients with previously untreated AML, refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEBT).METHODSThe MFAC regimen was comprised of gemtuzumab (Mylotarg™) (6 mg/m2 intravenously [i.v.] on Day 1); fludarabine and ara‐C (15 mg/m2 and 0.5 g/m2, respectively, twice daily on Days 2–6); and CSA (6 mg/kg loading dose before gemtuzumab, followed by 16 mg/kg continuous i.v. infusion on Days 1 and 2).RESULTSFifty‐nine evaluable patients were treated: 39 patients (66%) had AML and 20 patients (34%) had RAEB/RAEBT. Their median age was 57 years (range, 27–76 years). The MFAC regimen induced complete remission (CR) in 27 patients (46%) and CR with incomplete platelet recovery (CRp) in 1 patient (2%). The median survival period is 8 months. At 12 months, the survival rate is 38% and the event‐free survival rate in patients with CR/CRp is 27%. Infections complicated 38% of the courses of chemotherapy. Grade 3/4 toxicity included hyperbilirubinemia in 31% and transaminitis in 7% of the patients. Four patients (7%) developed hepatic venoocclusive disease (VOD).CONCLUSIONSThe MFAC regimen may merit further study in patients with AML if measures to avoid and/or treat VOD can be incorporated into the regimen. Cancer 2003;97:1481–7. © 2003 American Cancer Society.DOI 10.1002/cncr.11239

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“…Alternatively, when the PK is not sufficient to identify all parameters, some of these may be fixed if an estimation of their values (or their potential range) is available. For, example, based on the TMDD model, 36 we expect the value of K M to be larger or equal to K D (i.e., the antibody concentration that results in an elimination rate equal to 50% of V max must be at least equal to the concentration required to bind 50% of the target when antibody is in excess). Based on this, the value of K D can be used to provide a lower bound for the range of possible values of K M .…”

Section: Resultsmentioning

confidence: 99%

“…33-35 In the PK-RO model, the V max parameter represents the amount of antibody that is cleared by target when the target is fully saturated and can be associated with the target expression level. Based on this, a range of values for V max was used to assess the impact of possible differences in antigenic burden in patients 36 . As shown in Figure 1, CD33 expression levels measured by flow cytometry appear to be comparable or higher in human AML versus monkey monocytes, granulocytes and normal hematopoietic stem cell (HSCs).…”

Section: Resultsmentioning

confidence: 99%

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

Figueroa

Leipold

Leong

et al. 2018

mAbs

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For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

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Differences in CD33 Intensity Between Various Myeloid Neoplasms

Cited by 117 publications

References 22 publications

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high‐risk myelodysplastic syndromes

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

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