The CD37-targeted antibody–drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model

Beckwith, Kyle A.; Frissora, Frank; Stefanovski, Matthew; Towns, William H.; Cheney, Carolyn; Mo, Xiaokui; Deckert, Jutta; Croce, Carlo M.; Flynn, Joseph M.; Andritsos, Leslie A.; Jones, Jeffrey A.; Maddocks, Kami J.; Lozanski, Gerard; Byrd, John C.; Muthusamy, Natarajan

doi:10.1038/leu.2014.32

Cited by 34 publications

(37 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…29 The disadvantage of the long disease latency was overcome by transferring splenic leukocytes or B cells from leukemic mice into syngeneic or immunodeficient recipient mice. 34,84,87,[90][91][92][93][94][95][96][97][98][99] Generally, transplanted animals developed a frank leukemia within a few weeks or months. Together with xenograft models of CLL, 100 such transfer experiments represent reproducible systems for the elucidation of the efficacy and mechanism of action of novel therapies.…”

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

“…84 Finally, marked antileukemic effects have recently been reported for the inhibitor of nuclear export KPT-185 and the antibody drug conjugate IMGN529. 95,97 KPT-185 acts by blocking the activity of the nuclear exporter chromosome region maintenance 1 protein, or exportin1 (CRM1/ XPO1), which is a downstream mediator of microenvironmental signals sustaining CLL cell survival and growth. 97 Administration of the small molecule to SCID mice engrafted with leukemic B cells from Em-TCL1 mice improved survival of those mice.…”

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

“…A benefit in terms of overall survival has also been observed in CD37 transgenic mice engrafted with CD37 3 Em-TCL1 leukemia on treatment with IMGN529, which consists of the cytotoxic anti-CD37 antibody and the antimicrotubule agent DM1 that exerts an antiproliferative effect. 95 Forced induction of apoptosis. A major pathogenic mechanism in CLL development constitutes the resistance of the tumor cells to apoptosis.…”

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

See 2 more Smart Citations

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Simonetti

Bertilaccio

Ghia

et al. 2014

Blood

View full text Add to dashboard Cite

Mouse models that recapitulate human malignancy are valuable tools for the elucidation of the underlying pathogenetic mechanisms and for preclinical studies. Several genetically engineered mouse models have been generated, either mimicking genetic aberrations or deregulated gene expression in chronic lymphocytic leukemia (CLL). The usefulness of such models in the study of the human disease may potentially be hampered by species-specific biological differences in the target cell of the oncogenic transformation. Specifically, do the genetic lesions or the deregulated expression of leukemia-associated genes faithfully recapitulate the spectrum of lymphoproliferations in humans? Do the CLL-like lymphoproliferations in the mouse have the phenotypic, histological, genetic, and clinical features of the human disease? Here we compare the various CLL mouse models with regard to disease phenotype, penetrance, and severity. We discuss similarities and differences of the murine lymphoproliferations compared with human CLL. We propose that the Eμ-TCL1 transgenic and 13q14-deletion models that have been comprehensively studied at the levels of leukemia phenotype, antigen-receptor repertoire, and disease course show close resemblance to the human disease. We conclude that modeling CLL-associated genetic dysregulations in mice can provide important insights into the molecular mechanisms of disease pathogenesis and generate valuable tools for the development of novel therapies.

show abstract

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

See 1 more Smart Citation

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Simonetti

Bertilaccio

Ghia

et al. 2014

Blood

View full text Add to dashboard Cite

show abstract

“…In B cells, the actions of CD37 contribute to development of humoral immunity (9)(10)(11). Moreover, CD37 is a target for novel immunotherapies to treat B cell malignancies (12)(13)(14)(15)(16)(17)(18). CD37 has also been shown to control functions in T cells and dendritic cells (19)(20)(21)(22).…”

mentioning

confidence: 99%

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Wee

Schulze

Jones

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin–dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1–adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.

show abstract

“…77,78 An anti-CD37 antibody-drug conjugate IMGN529 is being studied in R/R CLL in a phase I study (NCT01534715). 79 Another CD37 directed therapy is BI 836826 an anti-CD37 mAb which is being studied in a phase I study (NCT01296932). 80 Another cell surface target CD23 is expressed on CLL cells and functions as an immunoglobulin E (IgE) receptor.…”

Section: Immunomodulators and Other Immune Based Treatments In Cllmentioning

confidence: 99%

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Sethi¹,

Reddy²

2017

Oncology &Amp; Hematology Review (US)

View full text Add to dashboard Cite

U ntil recently, chemoimmunotherapy has been the mainstay of treatment approach in chronic lymphocytic leukemia (CLL) patients requiring intervention. With the emergence of targeted treatments, there has been a shift in CLL therapy. With a better understanding of disease biology and risk stratification, a tailored approach based on patient age and comorbidities has evolved over time. The development of new and potent, next generation CD20 antibodies has refined therapy options especially for elderly unfit patients. Furthermore, agents targeting important pathways involved in proliferation and survival of CLL cells including B-cell receptor (BCR) signaling have provided additional treatment options in traditionally chemo-refractory CLL. Given the rapidly expanding repertoire of drugs, current research is focused on optimizing treatment sequence, duration of treatment and assessing long-term toxicities. Several immune mediated therapies are emerging and new combinations are being tested to re-establish antitumor immune effector response in CLL. While embracing the advances in CLL therapy, a few longstanding lessons remain. There is still little role of treatment of asymptomatic individuals. This review presents an overview of current and emerging drug therapies in the rapidly changing area of CLL treatment. Keywords CLL, novel agents, targeted therapyDisclosure: Tarsheen K Sethi and Nishitha M Reddy have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. In those that meet criteria for treatment, important considerations include: patient age, performance status, comorbidities, and presence of chromosomal aberrations. Recent advancements in the understanding of disease biology have highlighted the importance of several potentially targetable pathways contributing to disease pathogenesis such as aberrant activation of BCR signaling pathway, anti-apoptotic BCL2 pathway, and the role of the microenvironment. These novel agents have expanded the repertoire for patients ineligible for chemoimmunotherapy (CIT) due to age or comorbidities and those with poorly responsive disease (high risk genomics such as del [17p]).This review aims to outline the role of standard CIT, targeted agents and ongoing studies of novel agents defining the present landscape of CLL drug treatment. Currently approved therapies and general tr...

show abstract

The CD37-targeted antibody–drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model

Cited by 34 publications

References 35 publications

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Contact Info

Product

Resources

About