A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia

Byrd, John C.; Pagel, John M.; Awan, Farrukh T.; Forero, Andres; Flinn, Ian W.; Deauna‐Limayo, Delva; Spurgeon, Stephen E.; Andritsos, Leslie A.; Gopal, Ajay K.; Leonard, John P.; Eisenfeld, Amy J.; Bannink, Jeannette; Stromatt, Scott; Furman, Richard R.

doi:10.1182/blood-2013-07-512137

Cited by 67 publications

(43 citation statements)

References 24 publications

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“…27 Besides CD20, another target being explored is CD37, in which 1 monoclonal antibody (BI 836826) and 1 therapeutic protein (Tru-016) are under investigation; Tru-016 has shown an overall response rate of 20% in a phase 1 study. 28 As well, several other CD19 antibodies are in clinical trials with varying modifications to enhance antibody activity. Responses to XmAb5574 were fairly durable as well, especially given the limited duration of exposure to antibody in most patients.…”

Section: Discussionmentioning

confidence: 99%

A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL

Woyach

Awan

Flinn

et al. 2014

Blood

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• XmAb5574 is an Fc-engineered CD19 monoclonal antibody that is well tolerated as a single agent in patients with relapsed or refractory CLL.• XmAb5574 has preliminary efficacy as a single agent in CLL and is of interest for further study in this disease.CD19 is ubiquitously expressed on chronic lymphocytic leukemia (CLL) cells and is therefore an attractive candidate for antibody targeting. XmAb5574 (aka MOR00208) is a novel humanized CD19 monoclonal antibody with an engineered Fc region to enhance Fcg receptor binding affinity. Here we report results of a first in human phase 1 trial of XmAb5574 in patients with relapsed or refractory CLL. Twenty-seven patients were enrolled to 6 escalating dose levels, with expansion at the highest dose level of 12 mg/kg. Nine doses of XmAb5574 were infused over 8 weeks. No maximal tolerated dose was reached, and the drug was generally well tolerated, with infusion reactions of grades 1 and 2 being the most common toxicities. Grade 3 and 4 toxicities occurred in 5 patients and included neutropenia, thrombocytopenia, increased aspartate aminotransferase, febrile neutropenia, and tumor lysis syndrome. XmAb5574 showed preliminary efficacy, with 18 patients (66.7%) responding by physical examination criteria and laboratory studies, and 8 patients (29.6%) responding by computed tomography criteria. Pharmacokinetics showed a half-life of 14 days with clearance that was not dose-dependent. In conclusion, this phase 1 trial demonstrates safety and preliminary efficacy of a novel Fc-engineered CD19 monoclonal antibody XmAb5574 and justifies movement into the phase 2 setting. This trial was registered at www.clinicaltrials.gov as #NCT01161511. (Blood. 2014;124(24):3553-3560)

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Section: Discussionmentioning

confidence: 99%

A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL

Woyach

Awan

Flinn

et al. 2014

Blood

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“…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).…”

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confidence: 99%

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

Wee

Schulze

Jones

et al. 2015

The Journal of Immunology

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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.

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“…therapeutic consisting of an IgG1 variable region and a small, engineered constant region, allowing for better tumor penetration. Otlertuzumab was well tolerated but produced modest activity as a single agent in CLL in a recently published phase I study (37). CD74 is the invariant chain of the MHC class II molecule and is expressed in non-Hodgkin lymphoma.…”

Section: Other Antibody-based Therapy In Indolent Lymphomasmentioning

confidence: 99%

Are We Nearing an Era of Chemotherapy-Free Management of Indolent Lymphoma?

Bachy

Salles

2014

Clinical Cancer Research

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Indolent B-cell lymphomas are heterogeneous, comprising three grades of follicular lymphoma, small lymphocytic lymphoma, Waldenst€ om macroglobulinemia, marginal zone lymphoma, and most recently, possibly low proliferative mantle cell lymphoma. These lymphomas are characterized by a high responsiveness to chemotherapy or immunochemotherapy; however, in most cases, conventional therapy might not offer a cure. Furthermore, the patient's age at diagnosis, at time to first or subsequent relapses, as well as potential comorbidities often preclude the use of chemotherapy. Recent progress has been made in our understanding of dysregulated pathways and immunologic antitumor responses in indolent lymphoma. Major therapeutic advances have been achieved in the development of nonchemotherapeutic agents, making "chemo-free" treatment a near-future reality. In this article, we highlight these promising approaches, such as the combination of anti-CD20 antibodies with immunomodulatory drugs, with mAbs directed against other surface antigens such as CD22, with immunomodulatory antibodies such as PD-1, or with inhibitors of key steps in the B-cell receptor pathway signaling. However, the cost of such therapies and potential, albeit manageable, toxicity should be considered. Phase III trials will confirm the benefit of these new treatment strategies that do not require a chemotherapeutic drug and help us identify their exact place in the therapeutic armamentarium for indolent lymphoma. Here we focus on follicular lymphoma, which is the most frequent subtype of indolent lymphoma and for which an increasing body of evidence has emerged that supports the dawn of a new era of chemotherapy-free treatment.

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A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia

Abstract: Key Points Otlertuzumab (formerly TRU-016) has modest single-agent activity in symptomatic treated and untreated CLL. Otlertuzumab demonstrates an acceptable safety profile, providing rationale for combination with other effective CLL therapies.

Cited by 67 publications

References 24 publications

A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL

A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL

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

Are We Nearing an Era of Chemotherapy-Free Management of Indolent Lymphoma?

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