Targeting CD19: the good, the bad, and CD81

Velasquez, Mireya Paulina

doi:10.1182/blood-2016-11-749143

Cited by 7 publications

(5 citation statements)

References 8 publications

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“…Similar mutations in CD81 hinder the accurate glycosylation of its CD19 partner, suggesting that the open conformation is also required for CD81 function; defective CD19 maturation, including misglycosylation, results in CD19 immune escape in CAR-T immunotherapy, a major resistance problem for patients with acute lymphoblastic leukemia (Fischer et al, 2017;Velasquez & Gottschalk, 2017). Taken together, the open conformation is critical for different tetraspanin functions in cellular and therapeutic processes.…”

Section: Cd53-assisted B-cell Migrationmentioning

confidence: 99%

“…There are 33 tetraspanin members identified in the human genome. The well-studied CD81 is required for sperm-egg fusion during the fertilization process (Sutovsky, 2009), for cell composition regulation in the central nervous system (Geisert et al, 2002;Charrin et al, 2009), and for maturation of CD19 (Maecker & Levy, 1997;Shoham et al, 2003Shoham et al, , 2006Bagashev et al, 2018), a major immunotherapy target against lymphoma and leukemia (Park et al, 2016;Braig et al, 2017;Velasquez & Gottschalk, 2017). Most tetraspanins, including CD81, are widely distributed in cells and tissues.…”

Section: Introductionmentioning

confidence: 99%

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Open conformation of tetraspanins shapes interaction partner networks on cell membranes

et al. 2020

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Tetraspanins, including CD53 and CD81, regulate a multitude of cellular processes through organizing an interaction network on cell membranes. Here, we report the crystal structure of CD53 in an open conformation poised for partner interaction. The large extracellular domain (EC2) of CD53 protrudes away from the membrane surface and exposes a variable region, which is identified by hydrogen–deuterium exchange as the common interface for CD53 and CD81 to bind partners. The EC2 orientation in CD53 is supported by an extracellular loop (EC1). At the closed conformation of CD81, however, EC2 disengages from EC1 and rotates toward the membrane, thereby preventing partner interaction. Structural simulation shows that EC1‐EC2 interaction also supports the open conformation of CD81. Disrupting this interaction in CD81 impairs the accurate glycosylation of its CD19 partner, the target for leukemia immunotherapies. Moreover, EC1 mutations in CD53 prevent the chemotaxis of pre‐B cells toward a chemokine that supports B‐cell trafficking and homing within the bone marrow, a major CD53 function identified here. Overall, an open conformation is required for tetraspanin–partner interactions to support myriad cellular processes.

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Section: Cd53-assisted B-cell Migrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Open conformation of tetraspanins shapes interaction partner networks on cell membranes

et al. 2020

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“…The presence and intensity of CD19 can be altered after treatment with CD19-targeted immunotherapies [ 11 ]. There are several reported mechanisms for the disappearance of CD19 at the time of relapse, including convergence of acquired mutations and alternative splicing of CD19 [ 12 ], loss of heterozygosity in CD19 gene at the time of CD19-negative relapse [ 13 ], retention of misfolded protein in the endoplasmic reticulum [ 8 ], and loss of CD81 expression which is required for CD19 trafficking [ 14 ]. All five patients reported here had CD19 expression at diagnosis, ranging from 71% to 99%.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Follow up of Blinatumomab in Older Patients with B-Cell Acute Lymphoblastic Leukemia

Kathari,

An,

Dougherty

et al. 2024

Pharmaceuticals

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Older adults who are diagnosed with acute lymphoblastic leukemia (ALL) and are treated with chemotherapy generally have poor outcomes. Blinatumomab is a CD19/CD3 bispecific T-cell engager that has been approved for the treatment of B-cell ALL in the relapsed/refractory setting or in patients with minimal residual disease (MRD) positivity. We previously reported on a small cohort of older adults with newly diagnosed Philadelphia chromosome negative B-cell ALL who were treated with blinatumomab monotherapy in the first line setting. This is a long-term follow up of those patients and their clinical courses. All five patients achieved complete remission (CR) after one cycle of blinatumomab, and three were MRD-negative. Two patients completed three cycles of blinatumomab, two patients completed four cycles of blinatumomab, and one patient completed 17 cycles of blinatumomab total. In the last four years, four of these patients had relapsed disease requiring additional therapy. Two patients are alive after 61 months and 57 months since their first cycle of blinatumomab. Two of the patients died at 10 months and one died at 20 months. Here we describe the long-term clinical courses of these patients.

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“…This CD81-CD19 interaction, dynamically regulated upon B cell activation [ 79 ], is essential to the correct exposure of CD19 on the surface of B cells. Loss of CD81 expression results in an intracellular accumulation of CD19 [ 80 ]. Similarly, a mutation in the CD81 gene leads to the expression of a truncated protein which does not enable CD19 maturation and cell surface expression [ 81 ].…”

Section: Cd81 Biology Trafficking and Signalingmentioning

confidence: 99%

Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases

Bailly

Thuru

2023

Cancers

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Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 and Chikungunya virus, which exploits the large extracellular loop EC2 for cell entry. CD81 is also an anticancer target implicated in cancer cell proliferation and mobility, and in tumor metastasis. CD81 signaling contributes to the development of solid tumors (notably colorectal, liver and gastric cancers) and has been implicated in the aggressivity of B-cell lymphomas. A variety of protein partners can interact with CD81, either to regulate attachment and uptake of viruses (HCV E2, claudin-1, IFIM1) or to contribute to tumor growth and dissemination (CD19, CD44, EWI-2). CD81-protein interactions can be modulated with molecules targeting the extracellular domain of CD81, investigated as antiviral and/or anticancer agents. Several monoclonal antibodies anti-CD81 have been developed, notably mAb 5A6 active against invasion and metastasis of triple-negative breast cancer cells. CD81-EC2 can also be targeted with natural products (trachelogenin and harzianoic acids A-B) and synthetic compounds (such as benzothiazole-quinoline derivatives). They are weak CD81 binders but offer templates for the design of new compounds targeting the open EC2 loop. There is no anti-CD81 compound in clinical development at present, but this structurally well-characterized tetraspanin warrants more substantial considerations as a drug target.

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Targeting CD19: the good, the bad, and CD81

Cited by 7 publications

References 8 publications

Open conformation of tetraspanins shapes interaction partner networks on cell membranes

Open conformation of tetraspanins shapes interaction partner networks on cell membranes

Long-Term Follow up of Blinatumomab in Older Patients with B-Cell Acute Lymphoblastic Leukemia

Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases

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