A phase 1/2 trial of ublituximab, a novel anti‐<scp>CD</scp>20 monoclonal antibody, in patients with B‐cell non‐Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab

Sawas, Ahmed; Farber, Charles M.; Schreeder, Marshall T.; Khalil, Mazen; Mahadevan, Daruka; Deng, Chao; Amengual, Jennifer E.; Nikolinakos, Petros; Kolesar, Jill M.; Kuhn, John G.; Sportelli, Peter; Miskin, Hari P.; O’Connor, Owen A.

doi:10.1111/bjh.14534

Cited by 67 publications

(38 citation statements)

References 44 publications

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“…Ublituximab has completed several Phase 1 and 2 clinical trials against B cell malignancies. In a Phase 1/2 clinical trial in patients with B cell NHL or CLL previously treated with rituximab, ublituximab was well tolerated and efficacious 127 . Currently, it is in several clinical trials in combination with other drugs for treatment of patients with CLL.…”

Section: Therapeutic Afucosylated Antibody Drugs Approved For Market mentioning

confidence: 99%

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Pereira

Chan

Lin

et al. 2018

mAbs

255

211

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Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy. This review discusses the relevance of antibody core fucosylation to ADCC, different strategies to produce afucosylated antibodies, and an update of afucosylated antibody drugs currently undergoing clinical trials as well as those that have been approved.

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Section: Therapeutic Afucosylated Antibody Drugs Approved For Market mentioning

confidence: 99%

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Pereira

Chan

Lin

et al. 2018

mAbs

255

211

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“…59 Similar results have been observed with the type I Fc-optimized mAb ublituximab. 58 A large OBZ phase 3 trial included untreated CLL patients, randomized chlorambucil vs chlorambucil-RTX vs chlorambucil-OBZ. 8,60 An increase in complete response rate, undetectable minimal residual disease, and PFS were observed with the OBZ arm compared with RTX.…”

Section: How To Interpret the Results Of Obz Clinical Trials?mentioning

confidence: 99%

“…As far as we know, a G1e5 variant of RTX has never been clinically developed. Ocaratuzumab and ublituximab (Table 2), which are Fc-modified type I anti-CD20 mAbs ( Figure 1B), could be considered as surrogate comparators; unfortunately, their clinical development is now interrupted or is not so far advanced, 58 respectively. On the other side, because no naked Fc-unmodified type II anti-CD20 recombinant mAb ( Figure 1C) is under clinical development, it would be necessary to compare OBZ to ocaratuzumab and ublituximab to definitely appreciate the actual advantage of type II anti-CD20 mAbs.…”

Section: What Is the Right Obz Comparator?mentioning

confidence: 99%

“…Interestingly, ublituximab also induces a high incidence of IRR in B-CLL patients. 58 It remains to be determined whether the IRRs observed with these "FcgR engagers" are mechanistically similar to those commonly observed with the T-cell engagers (chimeric antigen receptor T cells, bispecific antibodies) and whether they would also benefit from IL-6Ra blockade therapy using tocilizumab, 71 which is currently under investigation (NCT02336048). In this context, the role and the impact of the direct cell death induced by OBZ as a prototypical type II anti-CD20 mAb remains to be determined.…”

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confidence: 96%

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Obinutuzumab: what is there to learn from clinical trials?

Cartron

Watier

2017

Blood

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Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL). Rituximab (RTX) is frequently considered as its "ancestor" and OBZ clinical development was justified by the importance of FcgRIIIAmediated mechanisms in RTX clinical activity. However, RTX differs from OBZ in 2 critical independent properties: being a type I anti-CD20 mAb and not being Fcoptimized. Moreover, the use of a different dosing regimen for RTX and OBZ further complicates any interpretation of clinical results. The results obtained for OBZ in CLL provide new arguments for FcgRIIIAmediated mechanisms when the target antigen is expressed at a low density. Results of OBZ in FL confirm the interest for FcgRIIIA-mediated mechanisms, with some limitations, some of them being possibly due to lack of OBZ-induced complement activation. The situation in diffuse large B-cell lymphoma is deceiving, as the possible gains of activity of OBZ appear to be annihilated by the lack of complement activation. Although RTX was by chance an anti-CD20 mAb with equilibrated pharmacodynamic properties, the reinforcement of some of these properties, which has been done at the expense of complement activation, has conferred an advantage in some B-cell disorders while restricting OBZ indications. The OBZ story nicely demonstrates that the future of naked mAbs is to design agents with optimized and tailored properties, and that this must be done step by step, with a full clinical validation. (Blood. 2017;130(5):581-589) Introduction Obinutuzumab (OBZ) is the first recombinant type II anti-CD20 and immunoglobulin G1 (IgG1) Fc-optimized monoclonal antibody (mAb) approved by the US Food and Drug Administration (FDA) and European Medicines Agency. It is currently labeled in first-line chronic lymphocytic leukemia (CLL) patients in association with chlorambucil, and in combination with bendamustine followed by OBZ monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab (RTX)-containing regimen. RTX was the first anti-CD20 mAb approved and largely contributed to establish the therapeutic value of anti-CD20 strategies in almost all CD201 malignancies. Experimental studies demonstrated that RTX is able to induce CD20 1 cell death by several mechanisms.1 RTX is sometimes presented as the "ancestor" of OBZ. First of all, OBZ is in no way a RTX biosimilar: not only are their variable domains totally different but also, in addition, RTX does not recognize the same CD20 epitope as OBZ and is a human IgG1 non-Fc-optimized antibody, 2 characteristics independent from each other and having functional and pharmacological consequences that need to be taken into consideration when trying to compare the 2 drugs. OBZ development was largely based on the presumed importance of FcgRIIIA-mediated mechanisms in RTX clinical activity, this being mainly supported by the influ...

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“…Ublituximab is a novel Monoclonal antibodies (MAb) targeting a unique epitope on the CD20 antigen which produced in the rat cell line YB2/0. Sawas A et al [40] organized a phase 1/2 trial of ublituximab, in patients with relapsed/refractory B-NHL or CLL previously exposed to rituximab. 35 Patients with B-NHL (n = 27) and CLL (n = 8) had a median of 3 prior therapies are enrolled and received treatment of ublituximab.…”

Section: Ublituximabmentioning

confidence: 99%

Treatment strategies for diffusive large B-cell lymphoma

Linling¹,

Lingqing²,

Gu³

et al. 2018

Oncol Res Rev

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The treatment of diffusive large B-cell lymphoma (DLBCL) is generally based on multidrug chemotherapy, the association of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) has become the standard therapy for DLBCL since the 1970s. The outcome of DLBCL has been substantially enhanced by the addition of the anti-CD20 monoclonal antibody rituximab. However, there is still some patients failed to the first-line treatment, those were considered as relapsed/ refractory DLBCL, and thus we need to adjust the dose or change the therapeutics. In addition, different treatment strategies should be stratified according to age, the International Prognostic Index (IPI), performance status, stage, prognostic score and immunohistochemical biomarkers. Besides, many novel drugs are under investigation in DLBCL patients, especially CAR-T regimen will have great prospects for development.

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A phase 1/2 trial of ublituximab, a novel anti‐CD20 monoclonal antibody, in patients with B‐cell non‐Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab

Cited by 67 publications

References 44 publications

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Obinutuzumab: what is there to learn from clinical trials?

Treatment strategies for diffusive large B-cell lymphoma

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