Highly active CAR T cells that bind to a juxtamembrane region of mesothelin and are not blocked by shed mesothelin

Liu, Xiufen; Onda, Masanori; Watson, Nathan; Hassan, Raffit; Ho, Mitchell; Bera, Tapan K.; Jiang, Wei; Chakraborty, Anirban; Beers, Richard; Zhou, Qi; Shajahan, Asif; Azadi, Parastoo; Zhan, Jingyu; Xia, Di; Pastan, Ira

doi:10.1073/pnas.2202439119

Cited by 16 publications

(28 citation statements)

References 32 publications

(59 reference statements)

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“…B, Alignment of structures of six fl-MSLN-245 and one fl-MSLN, all independently determined and rendered as Cα traces, shows large differences toward the C-terminal part of the structure. C, Magnified view of the interactions between the C-terminal peptide antigen of MSLN and the Fab of Mab 15B6, reproduced from previously published data ( 34 ). The structure of the peptide (N584-S598), shown as a Van der Waal's surface overlaid with its stick model with carbon in orange, nitrogen in blue, oxygen in red, and sulfur in yellow.…”

Section: Resultsmentioning

confidence: 97%

“…D, Structure of the C-term/Fab(15B6) complex is rendered as a cartoon overlaid with a transparent surface. This panel is reproduced from previously published data ( 34 ). The light chain (L) is colored purple, and the heavy chain (H) is colored green.…”

Section: Resultsmentioning

confidence: 99%

“…The investigation of the mechanism of MSLN shedding from the cell surface led to identification of a C-terminal region of MSLN (residue 582–598; Fig. 1B ) that contains majority of the major protease cleavage sites and the development of mAb 15B6 targeting this region ( 45 ). mAb 15B6 is a mouse isotype IgG2bλ, which was found to prevent MSLN shedding.…”

Section: Resultsmentioning

confidence: 99%

“…The isolation of shed MSLN from either cultured A431/H9 cell culture media or patient ascites was carried out according to the procedure published previously ( 34 ). Briefly, an anti-MSLN column was prepared by covalently immobilizing 2 mg of SS1P, an anti-MSLN recombinant immunotoxin on a 1-mL column packed with N-hydroxy-succinimide–activated Sepharose resin.…”

Section: Methodsmentioning

confidence: 99%

“…This mAb is able to block MSLN shedding and does not bind to shed MSLN. In addition, it causes complete remission of MSLN-expressing tumors in a mouse model when used in CAR-T cells ( 34 ).…”

Section: Introductionmentioning

confidence: 99%

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Structures of Cancer Antigen Mesothelin and Its Complexes with Therapeutic Antibodies

Zhan

Lin

Watson

et al. 2023

Cancer Research Communications

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The tumor-associated antigen mesothelin is expressed at high levels on the cell surface of many human cancers, while its expression in normal tissues is limited. The binding of mesothelin to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. Immunotherapeutic strategies targeting mesothelin are being intensively investigated. Here, we report the crystal structures of mesothelin that reveal a compact, right-handed solenoid consisting of 24 short helices and connecting loops. These helices form a 9-layered spiral coil that resembles ARM/HEAT family proteins. Glycan attachments have been identified in the structure for all three predicted N-glycosylation sites and confirmed with samples from cell culture and patient ascites. The structures of full-length mesothelin and its complex with the Fab of MORAb-009 reveal the interaction of the antibody with the complete epitope, which has not been previously reported. The N-terminal half of mesothelin is conformationally rigid, suitable for eliciting specific antibodies, whereas its C-terminal portion is more flexible. The structure of the C-terminal shedding-resistant fragment of mesothelin complexed with a monoclonal antibody 15B6 displays an extended linear epitope and helps explain the protection afforded by the antibody for the shedding sites.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structures of Cancer Antigen Mesothelin and Its Complexes with Therapeutic Antibodies

Zhan

Lin

Watson

et al. 2023

Cancer Research Communications

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Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

Hofe

Yang

Jin

2023

iLABMED

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Chimeric antigen receptor (CAR) T cell therapy is a relatively new form of targeted therapy that has demonstrated impressive success in treating hematological malignancies. It has been challenging to translate this success to solid tumors. Reasons for this include barriers to delivery, tumor heterogeneity, cancer cells' ability to evade the immune system as well as identifying the optimal target. Most CAR T clinical trials have targeted well‐characterized cancer targets with significant preclinical and in some cases clinical validation. Published results from some of these trials show signs of anti‐cancer activity that warrant encouragement, but also caution, given instances of unacceptable toxicity. The narrow therapeutic window is complicated by the ability of CAR T cells to expand in patients regardless of dose. Here, we review those trials showing encouraging results in the context of target selection. It is clear that more specific tumor targeting is required, either by affinity tuning to avoid low‐level target expression in healthy cells, logic gating, or the identification of new targets that are more cancer specific.

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Application of CAR-T cell therapy targeting mesothelin in solid tumor treatment

Chen,

Sun,

2024

Discov Onc

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Chimeric antigen receptor (CAR)-T-cell therapy is one of the most effective immunotherapies. CAR-T-cell therapy has achieved great success in the treatment of hematological malignancies. However, due to the characteristics of solid malignant tumors, such as on-target effects, off-tumor toxicity, an immunosuppressive tumor microenvironment (TME), and insufficient trafficking, CAR-T-cell therapy for solid tumors is still in the exploration stage. Mesothelin (MSLN) is a molecule expressed on the surface of various solid malignant tumor cells that is suitable as a target of tumor cells with high MSLN expression for CAR-T-cell therapy. This paper briefly described the development of CAR-T cell therapy and the structural features of MSLN, and especially summarized the strategies of structure optimization of MSLN-targeting CAR-T-cells and the enhancement methods of MSLN-targeting CAR-T cell anti-tumor efficacy by summarizing some preclinical experiment and clinical trials. When considering MSLN-targeting CAR-T-cell therapy as an example, this paper summarizes the efforts made by researchers in CAR-T-cell therapy for solid tumors and summarizes feasible treatment plans by integrating the existing research results.

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Highly active CAR T cells that bind to a juxtamembrane region of mesothelin and are not blocked by shed mesothelin

Cited by 16 publications

References 32 publications

Structures of Cancer Antigen Mesothelin and Its Complexes with Therapeutic Antibodies

Structures of Cancer Antigen Mesothelin and Its Complexes with Therapeutic Antibodies

Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

Application of CAR-T cell therapy targeting mesothelin in solid tumor treatment

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