Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use

Kwun, Jean; Matignon, Marie; Manook, Miriam; Guendouz, Soulef; Audard, Vincent; Kheav, David; Poullot, Elsa; Gautreau, C.; Ezekian, Brian; Bodez, Diane; Damy, Thibault; Faivre, Laureline; Menouch, Dehbia; Yoon, Janghoon; Park, Jae Berm; Belhadj, Karim; Chen, Dongfeng; Bilewski, Alyssa M.; Yi, John S.; Collins, Bradley H.; Stegall, Mark D.; Farris, Alton B.; Knechtle, Stuart J.; Grimbert, Philippe

doi:10.1681/asn.2018121254

Cited by 101 publications

(105 citation statements)

References 50 publications

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“…To date, only subjective clinical reports have been published on the use of CD38 antibodies in desensitization and treatment of AMR. Kwun and colleagues reported the use of daratumumab in desensitization in a heart transplant candidate [69]. Multiple courses of plasmapheresis, high-dose IVIG, and rituximab result in no significant changes in HLA antibody levels (calculated Panel Reactive Antibody score [cPRA] 98%), with deterioration of clinical condition.…”

Section: Solid Organ Transplantationmentioning

confidence: 99%

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Martin

Corzo

Chiron

et al. 2019

Cells

118

151

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CD38 is a transmembrane glycoprotein with ectoenzymatic activity involved in regulation of migration, signal transduction, and receptor-mediated adhesion. CD38 is highly expressed on various malignant cells, including multiple myeloma (MM), and at relatively low levels in other tissues, making it a suitable target for therapeutic antibodies. Several anti-CD38 therapies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab (SAR650984), respectively. Studies have shown that anti-CD38 therapies are effective in the treatment of relapsed/refractory MM and are well tolerated, with infusion reactions being the most common side effects. They can be used as monotherapy or in combination with immunomodulatory agents, such as pomalidomide, or proteasome inhibitors to potentiate their activity. Here we examine isatuximab and several anti-CD38 agents in development that were generated using new antibody engineering techniques and that may lead to more effective CD38 targeting. We also summarize trials assessing these antibodies in MM, other malignancies, and solid organ transplantation. Finally, we propose that further research on the mechanisms of resistance to anti-CD38 therapy and the development of biomarkers and new backbone regimens with CD38 antibodies will be important steps in building more personalized treatment for patients with MM.

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Section: Solid Organ Transplantationmentioning

confidence: 99%

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Martin

Corzo

Chiron

et al. 2019

Cells

118

151

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“…In detail, obinutuzumab is able to overcome the low affinity of certain polymorphisms of the FcGamma receptor 3A on effector cells, hence improving antibody-dependent cytotoxicity in a greater proportion of patients. Clinically, obinutuzumab induces more profound and lasting remission, with an almost twofold higher complete response rate in patients treated for indolent nonHodgkin lymphoma [ 15 ] and may also be more efficient than rituximab in autoimmune diseases [ 16 – 18 ].…”

Section: Discussionmentioning

confidence: 99%

A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome

et al. 2020

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Background Steroid-sensitive nephrotic syndrome (SSNS) is, in most patients, a chronic disease with 80% experiencing at least one relapse after first flare. B cell depletion using rituximab is effective in preventing relapse in steroid-dependent (SDNS) patients but fails to maintain long-term remission following B cell recovery, possibly due to development of autoreactive long-lived plasma cells. We investigated sequential combination of antiCD20 antibody targeting all B cell subsets, and antiCD38 antibody with high plasma cell cytotoxicity in patients with uncontrolled SDNS after failure of one or several attempts at B cell depletion. Methods Fourteen patients with median disease duration 7.8 years received 1000 mg/1.73 m 2 obinutuzumab followed by 1000 mg/1.73 m 2 daratumumab 2 weeks later. Oral immunosuppression was discontinued within 6 weeks, and biological monitoring performed monthly until B cell recovery. Results Median age at treatment was 11.0 [IQR 10.4–14.4] years. B cell depletion was achieved in all patients, and B cell reconstitution occurred in all at median 9.5 months after obinutuzumab injection. After median follow-up 20.3 months (IQR 11.5–22.6), 5/14 patients relapsed including 4 within 100 days following B cell repletion. Relapse-free survival was 60% at 24 months from obinutuzumab infusion. Mild infusion reactions were reported in 3/14 patients during obinutuzumab and 4/14 during daratumumab infusions. Mild transient neutropenia (500–1000/mm 3 ) occurred in 2/14 patients. Intravenous immunoglobulins were given to 12/14 patients due to hypogammaglobulinemia. Low IgA and IgM levels were noted in 8 and 14 patients, respectively. No severe infection was reported. Conclusion Global antiB cell strategy combining obinutuzumab and daratumumab induces prolonged peripheral B cell depletion and remission in children with difficult-to-treat SDNS. Electronic supplementary material The online version of this article (10.1007/s00467-020-04811-0) contains supplementary material, which is available to authorized users.

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“…They demonstrated that daratumumab effectively reduced DSAs and modestly prolonged graft survival posttransplant. However, all animals showed rapid antibody rebound and evidence for intense TCMR at month 1 15 …”

Section: Therapeutic Approaches To Treatment Of Amrmentioning

confidence: 96%

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection

et al. 2019

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Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell‐directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody‐mediated rejection (AMR) treatment by targeting CD20 found on B‐lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR.

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Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use

Cited by 101 publications

References 50 publications

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection

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