Relationship between CD33 expression, splicing polymorphism, and in vitro cytotoxicity of gemtuzumab ozogamicin and the CD33/CD3 BiTE® AMG 330.
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ABSTRACT:
SUBMITTER: Laszlo GS
PROVIDER: S-EPMC6355486 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Publications
Relationship between CD33 expression, splicing polymorphism, and <i>in vitro</i> cytotoxicity of gemtuzumab ozogamicin and the CD33/CD3 BiTE® AMG 330.
Laszlo George S GS Beddoe Mary E ME Godwin Colin D CD Bates Olivia M OM Gudgeon Chelsea J CJ Harrington Kimberly H KH Walter Roland B RB
Haematologica 20180816 2
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Project description:Preclinical and emerging clinical studies demonstrate that bispecific T-cell engaging (BiTE) antibody constructs can potently lyse targeted tumor cells, but the determinants for their activity remain incompletely understood. Using human acute myeloid leukemia (AML) cell lines engineered to overexpress individual T-cell ligands, we found that expression of the inhibitory ligands, PD-L1 and PD-L2, reduced the cytolytic activity of the BiTE antibody construct targeting CD33, AMG 330; conversely, expression of the activating ligands, CD80 and CD86, augmented the cytotoxic activity of AMG 330. Consistent with these findings, treatment with an activating antibody directed at the co-stimulatory T-cell receptor, CD28, significantly increased AMG 330-induced cytotoxicity in human AML cell lines. Using specimens from 12 patients with newly diagnosed or relapsed/refractory AML, we found that activation of CD28 also increased the activity of AMG 330 in primary human AML cells (P=0.023). Together, our findings indicate that T-cell ligands and co-receptors modulate the anti-tumor activity of the CD33/CD3 BiTE antibody construct, AMG 330. These findings suggest that such ligands/co-receptors could serve as biomarkers of response and that co-treatment strategies with pharmacological modulators of T-cell receptor signaling could be utilized to further enhance the activity of this targeted therapeutic.
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Project description:The CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliquots of primary AML samples were immunophenotypically characterized and subjected to various doses of AMG 330 in the presence or absence of healthy donor T-cells. After 48 hours, drug-specific cytotoxicity was quantified and correlated with CD33 expression levels, amounts of T-cells present, and other disease characteristics. AMG 330 caused modest cytotoxicity that was correlated with the amount of autologous T-cells (P = 0.0001) but not CD33 expression, as AMG 330 exerted marked cytotoxic effects in several specimens with minimal CD33 expression. With healthy donor T-cells added, AMG 330 cytotoxicity depended on the drug dose and effector:target (E:T) cell ratio. High cytotoxic activity was observed even with minimal CD33 expression, and AMG 330 cytotoxicity and CD33 expression correlated only at high E:T cell ratio and high AMG 330 doses (P<0.003). AMG 330 resulted in significantly higher cytotoxicity in specimens from patients with newly diagnosed AML than those with relapsed/refractory disease despite similar levels of CD33 on myeloblasts. AMG 330 cytotoxicity also appeared greater in specimens from patients with favorable-risk disease as compared to other specimens. Together, our data demonstrate that AMG 330 is highly active in primary AML specimens across the entire disease spectrum, while suggesting the presence of yet undefined, CD33-independent, relative resistance mechanisms in specific patient subsets.
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Project description: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.
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Project description:In September 2017, the US FDA announced re-approval of gemtuzumab ozogamicin (GO), a CD33-targeting immunoconjugate, for treatment of newly diagnosed and relapsed/refractory acute myeloid leukemia (AML). This is a very significant step toward defining new treatment regimens in AML, as the treatment has essentially stayed unchanged with the '7 + 3 induction regimen' (7 days cytarabine and 3 days of anthracycline) since 1973. GO is the first antibody-drug conjugate to receive FDA approval for treating cancer. This review article discusses the challenges faced and lessons learned during the journey of GO for AML treatment. Selected trials that have made significant contribution in our understanding of the most efficacious and safe use of GO for treating AML patients as well as factors influencing GO response are highlighted in this article.
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Project description:Acute myeloid leukemia (AML) is the most common acute leukemia amongst adults with a 5-year overall survival lower than 30%. Emerging evidence suggest that immune alterations favor leukemogenesis and/or AML relapse thereby negatively impacting disease outcome. Over the last years myeloid derived suppressor cells (MDSCs) have been gaining momentum in the field of cancer research. MDSCs are a heterogeneous cell population morphologically resembling either monocytes or granulocytes and sharing some key features including myeloid origin, aberrant (immature) phenotype, and immunosuppressive activity. Increasing evidence suggests that accumulating MDSCs are involved in hampering anti-tumor immune responses and immune-based therapies. Here, we demonstrate increased frequencies of CD14+ monocytic MDSCs in newly diagnosed AML that co-express CD33 but lack HLA-DR (HLA-DRlo). AML-blasts induce HLA-DRlo cells from healthy donor-derived monocytes in vitro that suppress T-cells and express indoleamine-2,3-dioxygenase (IDO). We investigated whether a CD33/CD3-bispecific BiTE® antibody construct (AMG 330) with pre-clinical activity against AML-blasts by redirection of T-cells can eradicate CD33+ MDSCs. In fact, T-cells eliminate IDO+CD33+ MDSCs in the presence of AMG 330. Depletion of total CD14+ cells (including MDSCs) in peripheral blood mononuclear cells from AML patients did not enhance AMG 330-triggered T-cell activation and expansion, but boosted AML-blast lysis. This finding was corroborated in experiments showing that adding MDSCs into co-cultures of T- and AML-cells reduced AML-blast killing, while IDO inhibition promotes AMG 330-mediated clearance of AML-blasts. Taken together, our results suggest that AMG 330 may achieve anti-leukemic efficacy not only through T-cell-mediated cytotoxicity against AML-blasts but also against CD33+ MDSCs, suggesting that it is worth exploring the predictive role of MDSCs for responsiveness towards an AMG 330-based therapy.
| S-EPMC6217777 | biostudies-literature
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| S-EPMC8561291 | biostudies-literature
Project description:BackgroundGemtuzumab ozogamicin (GO) was approved in 2017 in the US for the treatment of adults with newly diagnosed CD33-positive (CD33+) acute myeloid leukemia (AML), and adults and pediatric patients with CD33+ relapsed/refractory (R/R) AML.ObjectiveThe aim of this study was to estimate the budgetary impact of introducing GO to a 1-million-member US health plan over a 5-year period.MethodsWe developed models to estimate the impact of introducing GO in combination with conventional induction chemotherapy or as monotherapy for newly diagnosed AML, and as monotherapy for R/R AML. Models were built using data on drug costs and treatment-related outcomes obtained from published clinical trials and other publicly available sources. Results were reported on a per member/per year and per member/per month (PMPM) basis.ResultsBase-case results of the newly diagnosed model indicated that the addition of GO in the combination setting reduced the overall budget of a 1-million-member health plan. The estimated net cost (US$) savings ranged from $72,969 ($0.006 PMPM) in year 1 to $745,426 ($0.062 PMPM) in year 5. In the monotherapy setting, GO was associated with increased net costs ranging from $4118 (0.0003 PMPM) in year 1 to $31,885 ($0.003 PMPM) in year 5. Base-case results of the R/R AML model demonstrated increased net costs that ranged from $17,326 ($0.001 PMPM) in year 1 to $46,163 ($0.004 PMPM) in year 5. Scenario analyses in all settings indicated the budget impact was not overly sensitive to the selected input assumptions, with the exception of the scenario considering only the pharmacy budget impact in the combination setting.ConclusionsThe introduction of GO for newly diagnosed and R/R AML would have a minimal impact on the budget of a US health plan and could result in cost savings in the combination therapy setting for newly diagnosed AML.
| S-EPMC7790788 | biostudies-literature
Project description:Purpose Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C>T in the splice enhancer region regulates the expression of an alternatively spliced CD33 isoform lacking exon2 (D2-CD33), thus eliminating the CD33 IgV domain, which is the antibody-binding site for GO, as well as diagnostic immunophenotypic panels. We aimed to determine the impact of the genotype of this splicing polymorphism in patients with AML treated with GO-containing chemotherapy. Patients and Methods CD33 splicing single nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (No-GO arm, n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (GO arm, n = 408) as per the Children's Oncology Group AAML0531 trial. Results The rs12459419 genotype was CC in 415 patients (51%), CT in 316 patients (39%), and TT in 85 patients (10%), with a minor allele frequency of 30%. The T allele was significantly associated with higher levels of D2-CD33 transcript ( P < 1.0E-6) and with lower diagnostic leukemic cell surface CD33 intensity ( P < 1.0E-6). Patients with the CC genotype had significantly lower relapse risk in the GO arm than in the No-GO arm (26% v 49%; P < .001). However, in patients with the CT or TT genotype, exposure to GO did not influence relapse risk (39% v 40%; P = .85). Disease-free survival was higher in patients with the CC genotype in the GO arm than in the No-GO arm (65% v 46%, respectively; P = .004), but this benefit of GO addition was not seen in patients with the CT or TT genotype. Conclusion Our results suggest that patients with the CC genotype for rs12459419 have a substantial response to GO, making this a potential biomarker for the selection of patients with a likelihood of significant response to GO.
| S-EPMC5549451 | biostudies-literature
Project description:CD33 is expressed on the majority of acute myeloid leukemia (AML) leukemic blasts and is the target for gemtuzumab ozogamicin (GO), a toxin-conjugated anti-CD33 mAb. In the present study, we quantified the CD33 mean fluorescent intensity of leukemic blasts prospectively in 619 de novo pediatric AML patients enrolled in Children's Oncology Group GO-containing clinical trials and determined its correlation with disease characteristics and clinical outcome. CD33 expression varied more than 2-log fold; a median mean fluorescent intensity of 129 (range, 3-1550.07) was observed. Patients were divided into 4 quartiles, quartiles 1-4 (Q1-4) based on expression and disease characteristics and clinical response defined across quartiles. High CD33 expression was associated with high-risk FLT3/ITD mutations (P < .001) and was inversely associated with low-risk disease (P < .001). Complete remission (CR) rates were similar, but patients in Q4 had significantly lower overall survival (57% ± 16% vs 77% ± 7%, P = .002) and disease-free survival from CR (44% ± 16% vs 62% ± 8%, P = .022). In a multivariate model, high CD33 expression remained a significant predictor of overall survival (P = .011) and disease-free survival (P = .038) from CR. Our findings suggest that CD33 expression is heterogeneous within de novo pediatric AML. High expression is associated with adverse disease features and is an independent predictor of inferior outcome. The correlation between CD33 expression and GO response is under investigation. These studies are registered at www.clinicaltrials.gov as NCT00070174 and NCT00372593.
| S-EPMC3335378 | biostudies-literature