Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML

Pollard, Jessica A.; Alonzo, Todd A.; Loken, Michael R.; Gerbing, Robert B.; Ho, Phoenix A.; Bernstein, Irwin D.; Raimondi, Susana C.; Hirsch, Betsy A.; Franklin, Janet; Walter, Roland B.; Gamis, Alan S.; Meshinchi, Soheil

doi:10.1182/blood-2011-12-398370

Cited by 96 publications

(96 citation statements)

References 27 publications

(23 reference statements)

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“…Minimal deconjugation was confirmed by affinity capture measurements (data not shown). These results are similar to those reported in previous publications, 34 which showed that the average drug-to-antibody-ratio declined roughly 10% over the complete duration of the study and support the use of TAB concentrations for PK characterization of the anti-CD33 ADC. The TAB concentrations of anti-CD33 ADC observed in this toxicology study were consistent with PK observations in the monkey PKPD study.…”

Section: Resultssupporting

confidence: 91%

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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Section: Resultssupporting

confidence: 91%

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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“…Nowadays, the correlation between CD33 expression and GO response is being studied. Also, CD33 saturation is an important factor when considering the pharmacokinetics of GO and required doses [42]. In this review, not all included studies mentioned the mean expression of CD33, so no conclusions could be drawn regarding this relationship.…”

Section: Discussionmentioning

confidence: 94%

Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

Parigger

Zwaan

Reinhardt

et al. 2016

Expert Review of Anticancer Therapy

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Gemtuzumab ozogamicin, an anti-tumour antibiotic linked to an anti-CD33 antibody (Mylotarg®), has been well studied in AML in adults but to a lesser extent in children. No review has yet been published on the dose-related toxicity and efficacy of gemtuzumab ozogamicin in pediatric AML patients. Here we looked at 14 studies then scatterplots and linear regressions were used to estimate the relationship between the dose of gemtuzumab and its toxicity and efficacy. A nonsignificant increase in bilirubin level and in incidence of veno-occlusive disease was seen with higher doses of gemtuzumab ozogamicin when used as single-agent. In terms of efficacy, even a low dose of 3 mg/m 2 of gemtuzumab ozogamicin can have antileukemic effect, but available data do not allow conclusions on its dose-dependency. Data indicate that higher doses of gemtuzumab ozogamicin account for more adverse events. The data do not show that a high dose is required for anti-leukemic efficacy of gemtuzumab ozogamicin. This study also indicates that there seems to be a role for gemtuzumab ozogamicin in the treatment of pediatric AML and further studies are required to assess its optimal dose, schedule and balance between efficacy and side-effects. ARTICLE HISTORY

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“…27 Thus, rather than primarily relying on AML patient specimens to quantify the effect of CD33 on AMG 330-induced cytotoxicity, we took advantage of a well-controlled model system consisting of human AML cell lines expressing low levels of endogenous CD33 and corresponding sublines virally transduced to overexpress wildtype CD33 at various levels. Using this approach, our findings in engineered cell lines unequivocally demonstrate a quantitative relationship between CD33 expression and AMG 330-induced cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…25,26 Recent studies have confirmed that the amount of CD33 expressed on leukemic blasts varies significantly (several hundredfold) between individual AML patients. 27 Importantly, CD33 expression levels have been associated with prognostic risk factors such as cytogenetic and molecular abnormalities. 27 Thus, rather than primarily relying on AML patient specimens to quantify the effect of CD33 on AMG 330-induced cytotoxicity, we took advantage of a well-controlled model system consisting of human AML cell lines expressing low levels of endogenous CD33 and corresponding sublines virally transduced to overexpress wildtype CD33 at various levels.…”

Section: Discussionmentioning

confidence: 99%

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML

Laszlo

Gudgeon

Harrington

et al. 2014

Blood

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133

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Key Points• AMG 330 cytotoxicity against AML cells is proportional to the level of CD33 expression but is not affected by ABC transporter activity.• AMG 330 cytotoxicity is amenable to modulation and augmentation by clinically available drugs such as histone deacetylase or DNA methyltransferase I inhibitors.CD33 is a valid target for acute myeloid leukemia (AML) but has proven challenging for antibody-drug conjugates. Herein, we investigated the cellular determinants for the activity of the novel CD33/CD3-directed bispecific T-cell engager antibody, AMG 330. In the presence of T cells, AMG 330 was highly active against human AML cell lines and primary AML cells in a dose-and effector to target cell ratio-dependent manner. Using cell lines engineered to express wild-type CD33 at increased levels, we found a quantitative relationship between AMG 330 cytotoxicity and CD33 expression; in contrast, AMG 330 cytotoxicity was neither affected by common CD33 single nucleotide polymorphisms nor expression of the adenosine triphosphate-binding cassette (ABC) transporter proteins, P-glycoprotein or breast cancer resistance protein. Unlike bivalent CD33 antibodies, AMG 330 did not reduce surface CD33 expression. The epigenetic modifier drugs, panobinostat and azacitidine, increased CD33 expression in some cell lines and augmented AMG 330-induced cytotoxicity. These findings demonstrate that AMG 330 has potent CD33-dependent cytolytic activity in vitro, which can be further enhanced with other clinically available therapeutics. As it neither modulates CD33 expression nor is affected by ABC transporter activity, AMG 330 is highly promising for clinical exploration as it may overcome some limitations of previous CD33-targeted agents. (Blood. 2014;123(4):554-561) IntroductionAcute myeloid leukemia (AML) has served as a paradigm for the therapeutic use of monoclonal antibodies because of well-defined cell-surface antigens and easy tumor accessibility. The most investigated target so far is CD33, a myeloid differentiation antigen found on AML blasts in most patients and, perhaps, leukemic stem cells in some.1,2 Recent randomized phase 3 trials have demonstrated that the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), improves survival for some patients with newly diagnosed AML when added to conventional chemotherapy, with benefit primarily seen for those with favorable-risk disease and, to a smaller extent, intermediate-risk disease. [3][4][5] Although this experience indicates that CD33 is a valid target for this disease, 1,2 it is a challenging one for toxin-loaded antibodies due to its relatively low abundance, slow internalization, and drug transporter activity in AML cells. In fact, GO given alone or in combination with other chemotherapeutics is ineffective in many patients and, as a consequence, is currently no longer commercially available in many countries. 1,2Bispecific T-cell engager (BiTE) antibodies are a novel subclass of therapeutic single-chain antibodies. [6][7][8] What distinguishes BiTE antibodies ...

show abstract

Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML

Cited by 96 publications

References 27 publications

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

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

Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML

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