CD33 is expressed on plasma cells of a significant number of myeloma patients, and may represent a therapeutic target

Robillard, Nelly; Wuillème, Soraya; Lodé, Laurence; Magrangeas, Florence; Minvielle, Stéphane; Avet-Loiseau, Hervé

doi:10.1038/sj.leu.2403948

Cited by 32 publications

(26 citation statements)

References 9 publications

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“…(95)(96)(97) In the last decade, MFC immunophenotypic characterization of phenotypically aberrant PC has also been suggested to be a valuable tool for the detection of potential therapeutical targets on clonal PC and orientate tailored antibody-based therapies (and subsequent monitoring). Thus, MoAbs targeting the overall PC population (CD138) (98,99) or either growth factor receptors (IL-6 or IGF-1) (100,101) and other cell surface antigens expressed by aberrant PC (CD33, CD40, CD52, or CD74) (102)(103)(104)(105)(106)(107) and specific markers whose expression is restricted to subsets of PC (e.g. CD19, CD20, CD27, or CD117) have been developed and, several of them are currently under evaluation in phase I/II clinical trials (70,71).…”

Section: Utility Of Mfc In MM and Other Plasma Cell Dyscrasiasmentioning

confidence: 99%

Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell‐related disorders

Paiva

Almeida

Pérez-Andrés

et al. 2010

Cytometry Part B Clinical

180

149

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Section: Utility Of Mfc In MM and Other Plasma Cell Dyscrasiasmentioning

confidence: 99%

Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell‐related disorders

Paiva

Almeida

Pérez-Andrés

et al. 2010

Cytometry Part B Clinical

180

149

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“…To scale the parameters describing the target-mediated elimination (V max and K M ), differences in target expression and the antibody-target interaction across species were taken into account. The magnitude of the CD33 target sink in AML patients may be larger than that in normal monkeys either due to high receptor expression of the CD33 target on patient's blasts 31 or increased number of CD33-expressing cells 32 . In addition, heterogeneity in levels of CD33 expression is anticipated in patients.…”

Section: Resultsmentioning

confidence: 99%

“…We anticipate that AML patients may have a higher and more variable antigen burden than that observed in normal cynomolgus monkey 31 . Hence, a range of values of target capacity was studied, based on measured levels of expression.…”

Section: Discussionmentioning

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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“…A small number of studies have observed the expression of CD33 on plasma cell surfaces; however, the reactivity of the marker has been noted in 6.5-12% of patients with myeloma (10,11). The expression of CD33 in such patients is reported to be associated with certain clinical parameters; the CD33 + patient group had a lower survival rate compared to the CD33 -patient group, thus indicating the clinicopathological significance of CD33 expression (12).…”

Section: A B C D E F G Hmentioning

confidence: 99%

Small-lymphoid cells and myeloid antigen expression in a patient with IgG myeloma: A case report

et al. 2016

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Abstract. Multiple myeloma is defined as a malignant proliferation of a single clone of plasma cells resulting in monoclonal immunoglobulin production. Due to the number of plasma cell morphological variants, difficulty is often faced during morphological diagnosis. The current study describes the case of a 49-year-old woman presenting with atypical plasma cell morphology detected by a bone marrow examination. Flow cytometric immunophenotyping determined the nature of the neoplastic cells as monoclonal myeloma cells with myeloid antigen expression. Serum electrophoresis with immunofixation and subsequent clinical findings confirmed this diagnosis. Therefore, the immunophenotyping of plasma cells in myelomas may be useful for the diagnosis of cases with atypical plasma cell morphology.

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CD33 is expressed on plasma cells of a significant number of myeloma patients, and may represent a therapeutic target

Cited by 32 publications

References 9 publications

Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell‐related disorders

Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell‐related disorders

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

Small-lymphoid cells and myeloid antigen expression in a patient with IgG myeloma: A case report

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