Developments in the targeting of Claudin 6 in Antibody and CAR-T cell therapies

Claudin 6 (CLDN6) is an intercellular adhesion molecule that develops tight junctions all around cells and controls epidermal permeability, restricting the free passage of solutes and water via cells.

Claudin 6 overexpression in the epidermis causes defective permeability barrier function in homozygous mice, resulting in dehydration and death within 48 hours of birth. Claudin 6 is a cofactor for hepatitis C virus (HCV) entry, and overexpression of the protein in 293 T cells conferred susceptibility to HCV entry.

Earlier studies discovered that Claudin 6 was not detected in normal adult tissues. However, it was highly expressed in a range of solid tumor tissues like testicular cancer, ovarian cancer, and endometrial cancer. As a result, Claudin 6 is likely to follow Claudin 18.2, another Claudin family member that could be used to treat cancer.

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Developments in the targeting of Claudin 6 in antibody and CAR-T cell therapies

mRNA expression of Claudin 6 in human normal tissue (top) and cancer (bottom). Image from reference

Currently, drug research targeting Claudin 6 is displaying a scene of competition for discoveries.

Monoclonal antibody (mAb)

Ganymed was purchased by Astellas for $1.4 billion in 2016. Apart from being optimistic about IMAB362, which targets Claudin 18.2, and broadening its immuno-oncology pipeline, IMAB027 (ASP1650), which targets Claudin 6, is also significant.

IMAB027 binds to Claudin 6 specifically in preclinical studies, and as a single agent induces Claudin 6+ tumor cell death via ADCC and CDC, resulting in antitumor activity in vitro and in vivo.

Moreover, heterogeneous expression of Claudin 6 in tumors, chemotherapy sensitized cells to ADCC inducing by IMAB027, and IMAB027 in combination with chemotherapeutic agents could optimize the antitumor effect

A Phase I clinical trial in advanced ovarian cancer patients was completed (NCT02054351). In October 2020, a Phase II clinical trial was completed, but it was halted because the primary endpoint was not met.

Anti-Claudin 6 mAb GB-7008, developed by GENCHEM (Shanghai) and I-MAB Biopharma, is in preclinical development for testicular tumors and ovarian cancer.

Antibody-drug conjugate (ADC)

Antibody–drug conjugates (ADCs) are immunoconjugates. They include a monoclonal antibody bound to a cytotoxic drug (called the payload) through a chemical linker. Tumor cell line plasticity is the main mechanism of tumor recurrence or therapeutic resistance.

To avoid drug toxicity, highly plastic tumor cells can be phenotypically transformed to a drug-resistant state. Guangzhou Medical University’s Affiliated Cancer Hospital and Research Institute compared the plasticity of a hepatocellular carcinoma (HCC) cell line using Claudin 6 as a therapeutic target. As a result, a novel anti-Claudin 6 ADC with DM1 as a payload was created.

Preclinical data in HCC cell lines and primary tumors display that anti-Claudin 6 ADC includes potent antitumor efficacy in HCC treatment either as a single agent or jointly with sorafenib.

Bispecific antibody (bsAb)

The BioNTech team fabricated 6PHU3, a T-cell-engaging bispecific single-chain molecule [bi-(scFv)2] with anti-CD3 or anti-Claudin 6 specificities. It is targeted to induce T cells to kill Claudin 6+ tumor cells by triggering T cells and specifying its pharmacodynamic properties.

The in vivo efficacy experiments affirmed that the highly selective targeting of 6PHU3 is efficient. 6PHU3 is probably an efficient treatment for Claudin 6+ solid tumors.

Developments in the targeting of Claudin 6 in antibody and CAR-T cell therapies

6PHU3 binds to CLDN6 and CD3 selectively. Image from reference

CAR-T cell therapy

The accuracy specificity, high sensitivity, and strength of CAR to Claudin 6, a surface molecule, make Claudin 6 a perfect target for CAR-T cell therapy for solid cancers. Besides anti-Claudin 6/CD3 bsAb (BNT142), BioNTech’BNT211 is also known as a CAR-T cell therapy targeting Claudin 6.

It is utilized in the early clinical development for the treatment of solid tumors and is presently in Clinical Phase I/II.

Developments in the targeting of Claudin 6 in antibody and CAR-T cell therapies

Partial pipeline of BioNTech. Image from reference

Summary

Claudin 6 is explicitly silenced in healthy adult tissues, but abnormally activated and expressed in a variety of solid tumors with high medical needs. As a result, Claudin 6 is thought to be a promising cancer immunotherapy target.

The development of different drug types that target Claudin 6, such as mAbs, ADCs, bsAbs and CAR-T cell therapy, has given solid tumor immunotherapy new strategies and hope.

ACROBiosystems has been successful in developing HEK293 expressed full-length Claudin 6-VLP protein (Met 1-Val 220) through “FLAG” to aid drugs and therapies R&D targeting Claudin 6.

Product list

Source: ACROBiosystems

Molecule Cat. No. Product Description Application
Claudin-6 CL6-HF2G5 Human Claudin-6 / CLDN6 Full Length Protein-VLP (HEK293)New Immunization
ELISA
SPR/BLI
Cell-based Assay
VLP VLP-H52C5 Virus-Like Particle (VLP) isotype control VLP Isotype Control

 

Product features

  • Full-length Claudin 6 protein available with native and entire conformation
  • Ideal for immunization/ELISA/SPR/BLI/cell experiment etc.
  • Higher immunogenicity as a result of inherent characteristics of VLP
  • High biological activity is verified by binding to antibodies
  • 100 to 300 nm in size and high identity confirmed by DLS and could be utilized as an optimal target for phage display and dendritic cells

Verification data

Full-length Claudin 6-VLP protein (Cat. No. CL6-HF2G5)

High bioactivity verified by ELISA

Developments in the targeting of Claudin 6 in antibody and CAR-T cell therapies

Image Credit: ACROBiosystems

Immobilized Human Claudin-6 Full Length Protein-VLP (Cat. No. CL6-HF2G5) at 5 μg/mL (100 μL/well) can attach to Anti-Human Claudin-6 Antibody, Human IgG1 with a linear range of 0.01–0.625 μg/mL (QC tested).

High identity verified by DLS

Developments in the targeting of Claudin 6 in antibody and CAR-T cell therapies

Image Credit: ACROBiosystems

The mean peak Radius of Claudin 6-VLP (Cat. No. CL6-HF2G5) is 80–100 nm with more than 95% intensity as determined by dynamic light scattering (DLS).

References

  1. Kong F E., et al. Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLAUDIN 6 antibody-drug conjugate[J]. Science Translational Medicine, 2021, 13(579), doi.org/10.1126/scitranslmed.abb6282
  2. Junko Matsuzaki, Shashikant Lele, Kunle Odunsi&Takemasa TsujiIdentification of Claudin 6-specific HLA class I- and HLA class II-restricted T cellreceptors for cellular immunotherapy in ovarian cancer, OncoImmunology, 2022, 11:1, 2020983, doi.org/10.1080/2162402X.2021.2020983
  3. https://www.pharmacodia.com/
  4. https://investors.biontech.de/node/9121/html
  5. Christiane R. Stadler, Hayat Bähr-Mahmud, Laura M. Plum, Kathrin,Schmoldt, Anne C. Kölsch, Özlem Türeci &UgurSahin (2016) Characterization of the firstin-class T-cell-engaging bispecific single-chain antibody for targeted immunotherapy of solidtumors expressing the oncofetal protein Claudin 6, OncoImmunology, 5:3, e1091555, doi.org/10.1080/2162402X.2015.1091555

About ACROBiosystems

ACROBiosystems is a leading manufacturer of recombinant proteins and other critical reagents to support the development of target therapeutics. The company employs an application-oriented development strategy, with a particular focus on product design, quality control, and solution-based support. Our products and services enable anyone in the field of drug development to have a more intuitive and streamlined process.

To respond to the coronavirus pandemic, ACROBiosystems has developed SARS-CoV-2 antigens specifically designed and optimized for serological test kits, including Spike-derived antigen S1, RBD, and Nucleocapsid protein. Proteins have been supplied to diagnostic companies in large quantities.


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Last updated: Jun 6, 2022 at 5:28 AM

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