On Target is a recurring feature from STAT that dives deep into the most promising drug targets in oncology. This column is adapted from the new STAT Report: Targeting cancer: the new frontier of immunotherapy and precision oncology.
Targeted immunotherapies like CAR-T have been remarkably successful in combating blood cancers like chronic lymphocytic leukemia. But malignancies that involve solid tumors have proved far more challenging for these new technologies. As yet, there has been no engineered cell therapy for solid tumors, which make up the overwhelming majority of cancers and include breast, lung, pancreatic, ovarian and prostate cancers.
One of the biggest roadblocks has been finding the right molecular targets. These therapies work by killing any cell that carries a designated marker, so scientists need to find a molecular target that exists on cancer cells but is not present in healthy tissues – especially life-sustaining tissues like the heart or the brain.
Scientists have found few targets that fit this bill, but recently, a protein called claudin-6 or CLDN6 has been drawing the interest of researchers as one potential guide for immunotherapies. Several biotech and pharma companies have begun developing bispecific antibodies — engineered antibodies that can bind to two different antigens — or CAR-T cell therapies targeting CLDN6. BioNTech, whose founders helped discover the protein as a possible cancer antigen, is one of the most notable.
Researchers working with BioNTech presented data from a clinical trial of a CAR-T therapy targeting CLDN6 at the American Association of Cancer Research meeting in New Orleans in 2022. The trial showed that, with an immunologic boost from an mRNA vaccine, the therapy could shrink some solid tumors. BioNTech code-named the combination of the vaccine and therapy BNT211, and it remains one of the first examples of early efficacy from CAR-T cells in solid tumors, something that the cancer immunotherapy field has long struggled to achieve.
That data also helped put CLDN6 more firmly on the map as a target, said Martin Lehr, the CEO of Context Therapeutics, a biotech that is also developing drugs targeting CLDN6. “For me as an oncology drug developer, the BioNTech data was really exciting. It creates opportunities for companies like us,” he said.
In the 1990s, Özlem Türeci and her husband, Uğur Şahin, the co-founders of BioNTech, were mulling over how to find a viable target for solid tumors. Ideally, they knew, it would be a protein that wasn’t present in healthy tissues but was highly expressed on cancer cells. That gave them an idea. Cancer cells sometimes turn on embryonic genes, or genes that are only turned on during fetal development and then silenced after birth.
“We knew cancer cells like to activate embryonic genes because they make use of proliferation,” Türeci said.
So, if Türeci and her colleagues could find activated embryonic genes in cancer cells, that might yield a useful therapeutic target. In their search, “We got this set of interesting targets,” Türeci said. “One of them was claudin-6.”
Türeci and Şahin went on to found a company called Ganymede that was focused on building antibodies to CLDN6 and other targets, including one in the same protein group, claudin 18.2. Astellas Pharma acquired that company, along with its claudin assets, but it wasn’t the end of Türeci and Şahin’s interest in CLDN6. Later, after they created BioNTech, they turned back to CLDN6 and created more therapies targeting the protein, including BNT211, the CAR-T and mRNA vaccine combination.
CLDN6 is a member of the claudin family of proteins, involved with regulating cell permeability and adhesion and helping maintain the structure and shape of cells. While scientists know that CLDN6 is present during the development of a fetus, its exact function is not entirely clear. The protein helps cancer cells spread, Türeci said, “but we can’t explain fully how it promotes transformation of a cancer cell, for example. We do not know in-depth how CLDN6 functions. To understand this in-depth, it really is a project of a lifetime.”
Still, she added, “That’s not so relevant for us. We are more interested to find what molecules are stably expressed on cancer cells. If you are using immunotherapy to target such a molecule, it doesn’t really matter what it does, only that it is cancer cell selective.”
CLDN6 is present on nearly all testicular cancers and is also expressed on a significant proportion of ovarian cancers, non-small cell lung cancers, and gastric, breast, and endometrial cancers. It’s found in certain healthy adult tissues, like the pancreas and liver, but only at extremely low levels. “It’s really an ideal target in solid tumors,” Türeci said, adding, “There are not many of them. In the late ’90s, when we found CLDN6, we basically went through the entire genome, and there’s not much which compares to CLDN6 that you can find for solid tumors.”
In the last couple of years, more companies have begun investing in CLDN6 assets. “The field has gotten pretty exciting,” said Lehr of Context Therapeutics, a biotech that’s developing a CLDN6 bispecific antibody, a double-armed molecule that can bind to a T cell with one arm and to an immunotherapy target with the other arm. “We’ve seen an acceleration of companies entering the space,” Lehr said.
Xencor, NovaRock, Amgen, I-Mab, Chugai, Daiichi Sankyo, and AbbVie all have programs for CLDN6 compounds, he said. While these companies are taking different approaches, they will have to solve some of the same problems. For one, although CLDN6 is rarely expressed in normal adult tissues, it’s structurally very similar to another, related protein called CLDN9, which is expressed at high levels in the whole body.
An antibody or a CAR that cannot distinguish between CLDN6 and CLDN9 could potentially lead to severe toxicities for patients, since CLDN9 is widely present in healthy tissue. So far, that hasn’t happened with BioNTech’s BNT211, and Lehr said that he hasn’t seen it arise in Context’s research either. Amgen also presented data this year showing that its specific antibody could selectively bind against CLDN6, ignoring CLDN9.
Like other bispecific antibodies, Amgen and Context’s bispecifics can use CLDN6 to grab onto the cancer cell with one arm. The other arm of the bispecific engages a T cell using another protein present on the surface of T cells like CD3, and pulls the two cells into close proximity. “That permits the T cell to exert its tumor cell killing function,” Amgen said, while potentially disrupting CLDN6’s function in the cancer cell “associated with tumor cell proliferation, migration, and invasion.”
If companies can get these approaches to work, CLDN6 may help unlock some of the first cell therapies or bispecific antibody therapies for solid tumors.
Previous On Target columns explored synthetic biomarkers, TGF-beta, and immune checkpoint inhibitors.
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