[Inspiring Target] Breakthroughs of targeting Claudin 6 in mAb, bsAb, ADC, CAR-T cell therapy

mRNA expression of Claudin 6 in human normal tissue (top) and cancer (bottom)

At present, drugs research targeting Claudin 6 is showing a scene of competition for breakthroughs.

Monoclonal Antibody (mAb)

In 2016, Astellas spent $1.4 billion to acquire Ganymed. In addition to being optimistic about IMAB362 targeting Claudin 18.2 and expanding its immuno-oncology pipeline, its IMAB027 (ASP1650) targeting Claudin 6 is also important. In preclinical studies, IMAB027 binds with Claudin 6 specifically, and as a single agent induces Claudin 6+ tumor cell death via ADCC and CDC, thereby exerting antitumor activity in vitro and in vivo. Furthermore,heterogeneous expression of Claudin 6 in tumors, chemotherapy sensitized cells to ADCC inducing by IMAB027, and IMAB027 in combination with chemotherapeutic agents may enhance the antitumor effect. A Phase I clinical trial in patients with advanced ovarian cancer was completed (NCT02054351). A Phase II clinical trial was completed in October 2020, but it was terminated because it did not meet the primary endpoint.

The anti-Claudin 6 mAb GB-7008 from GENCHEM (Shanghai) and I-MAB Biopharma is in the preclinical development stage and is indicated for testicular tumors and ovarian cancer.

Antibody-drug Conjugate (ADC)

Antibody–drug conjugates (ADCs) are immunoconjugates comprised of a monoclonal antibody tethered to a cytotoxic drug (known as the payload) via a chemical linker. Tumor cell line plasticity is a key mechanism of therapeutic resistance and tumor recurrence. Highly plastic tumor cells can be phenotypically converted to a drug-resistant state to avoid drug toxicity. Affiliated Cancer Hospital and Research Institute of Guangzhou Medical University, based on Claudin 6 as a therapeutic target related to the plasticity of hepatocellular carcinoma (HCC) cell line, prepared a novel anti-Claudin 6 ADC with DM1 as payload. Preclinical data in HCC cell lines and primary tumors show that anti-Claudin 6 ADC has potent antitumor efficacy in HCC treatment either as a single agent or in combination with sorafenib.

Bispecific Antibody (bsAb)

The BioNTech team engineered 6PHU3, a T-cell-engaging bispecific single chain molecule (bi-(scFv)2) with anti-CD3/anti-Claudin 6 specificities.It is aiming to induce T cells to kill Claudin 6+ tumor cells by activating T cells and characterizing its pharmacodynamic properties. The in vivo efficacy experiments confirmed that the highly selective targeting of 6PHU3 is effective. 6PHU3 is likely to be an effective treatment for Claudin 6+ solid tumors.

6PHU3 binds to CLDN6 and CD3 selectively

CAR-T Cell Therapy

The high sensitivity, precise specificity, and potency of CAR to Claudin 6, a surface molecule, make Claudin 6 an ideal target for CAR-T cell therapy for solid cancers. In addition to anti-Claudin 6/CD3 bsAb (BNT142), BioNTech’BNT211 is a CAR-T cell therapy targeting Claudin 6. It is used in the early clinical development for the treatment of solid tumors and is currently in the Clinical Phase I/II.

Partial pipeline of BioNTech

Summary

Claudin 6 is strictly silenced in healthy adult tissues, but aberrantly activated in various solid tumors with high medical needs, showing high levels of expression. Therefore, Claudin 6 is considered as a promising target for cancer immunotherapy. The research on different drug types targeting Claudin 6 such as mAb, ADC, bsAb, and CAR-T cell therapy has brought new strategies and hope for solid tumor immunotherapy.

ACROBiosystems has successfully developed HEK293 expressed full-length Claudin 6-VLP protein (Met 1 - Val 220) via "FLAG" to support drugs and therapies R&D targeting Claudin 6.

>>> Learn more about “FLAG”: full-length multi-pass transmembrane proteins and technology platforms

References:

1,Kong F E, Li G M, Tang Y Q, 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: 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: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:10.1080/2162402X.2015.1091555