Gemtuzumab Ozogamicin, A Potent and Selective Anti-CD33 Antibody−Calicheamicin Conjugate for Treatment of Acute Myeloid Leukemia

Hamann, Philip R.; Hinman, Lois M.; Hollander, Irwin; Beyer, Carl F.; Lindh, Delores; Holcomb, Ryan E.; Hallett, William; Tsou, Hwei Ru; Upeslacis, Janis; Shochat, Dan; Mountain, Andrew; Flowers, David; Bernstein, Irwin D.

doi:10.1021/bc010021y

Cited by 523 publications

(423 citation statements)

References 20 publications

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“…One of the first examples of Abbased delivery is gemtuzumab ozogamicin (GO, Mylotarg or CMA-676), which consists of a humanized CD33 Ab covalently linked to a derivative of the potent DNA-damaging cytotoxic agent calicheamicin. 7,8 Calicheamicin induces cell death in its target cells by interaction with double-helical DNA in the minor groove causing site-specific double-stranded DNA cleavage at very low concentrations. 9 GO was initially developed for the treatment of patients with CD33-positive acute myeloid leukemia (AML) and the single-agent maximum tolerated dose was two infusions of 9 mg/m 2 with a 14-day interval.…”

Section: Introductionmentioning

confidence: 99%

The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells

et al. 2011

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We investigated whether the newly developed antibody (Ab) -targeted therapy inotuzumab ozogamicin (CMC-544), consisting of a humanized CD22 Ab linked to calicheamicin, is effective in pediatric primary B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells in vitro, and analyzed which parameters determine its efficacy. CMC-544 induced dose-dependent cell kill in the majority of BCP-ALL cells, although IC 50 values varied substantially (median 4.8 ng/ml, range 0.1-1000 ng/ml at 48 h). The efficacy of CMC-544 was highly dependent on calicheamicin sensitivity and CD22/CMC-544 internalization capacity of BCP-ALL cells, but hardly on basal and renewed CD22 expression. Although CD22 expression was essential for uptake of CMC-544, a repetitive loop of CD22 saturation, CD22/CMC-544 internalization and renewed CD22 expression was not required to achieve intracellular threshold levels of calicheamicin sufficient for efficient CMC-544-induced apoptosis in BCP-ALL cells. This is in contrast to studies with the comparable CD33 immunotoxin gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia (AML) patients, in which complete and prolonged CD33 saturation was required for apoptosis induction. These data suggest that CMC-544 treatment may result in higher response rates in ALL compared with response rates obtained in AML with Mylotarg, and that therefore clinical studies in ALL, preferably with multiple low CMC-544 dosages, are warranted.

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Section: Introductionmentioning

confidence: 99%

The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells

et al. 2011

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“…Both unconjugated 40 , 41 and conjugated antibodies 42-44 targeting CD33 have been previously studied in the clinic for treatment of AML. Lintuzumab is an unconjugated humanized IgG1 anti-CD33 antibody that was terminated during clinical development because of lack of activity as a single agent and failure to improve survival when used in combination with conventional chemotherapy 45 .…”

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

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Leong

et al. 2018

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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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“…Upon internalization, the acidic pH in endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0) leads to hydrolysis of the hydrazone and subsequent release of the drug 2,20 . The serum stability of hydrazone linkers, however, is poor 21,22 . The low clinical efficacy and the safety concerns of gemtuzumab ozogamicin were mainly attributed to this linker instability and premature drug release in the circulation 5,16,23 .…”

Section: Linker Chemistriesmentioning

confidence: 99%

Antibody–Drug Conjugates for Tumor Targeting—Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins

et al. 2015

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Antibody-drug conjugates (ADCs) have emerged as a promising class of anti-cancer agents, combining the specificity of antibodies for tumor targeting and the destructive potential of highly potent drugs as payload. An essential component of these immunoconjugates is a bifunctional linker capable of reacting with the antibody and the payload to assemble a functional entity. Linker design is fundamental, as it must provide high stability in the circulation to prevent premature drug release, but be capable of releasing the active drug inside the target cell upon receptor-mediated endocytosis. Although ADCs have demonstrated an increased therapeutic window, compared to conventional chemotherapy in recent clinical trials, therapeutic success rates are still far from optimal. To explore other regimes of half-life variation and drug conjugation stoichiometries, it is necessary to investigate additional binding proteins which offer access to a wide range of formats, all with molecularly defined drug conjugation. Here, we delineate recent progress with site-specific and biorthogonal conjugation chemistries, and discuss alternative, biophysically more stable protein scaffolds like Designed Ankyrin Repeat Proteins (DARPins), which may provide such additional engineering opportunities for drug conjugates with improved pharmacological performance.3

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Gemtuzumab Ozogamicin, A Potent and Selective Anti-CD33 Antibody−Calicheamicin Conjugate for Treatment of Acute Myeloid Leukemia

Cited by 523 publications

References 20 publications

The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells

The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells

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

Antibody–Drug Conjugates for Tumor Targeting—Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins

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