Our Science

αvβ6-Integrin is expressed by a variety of carcinomas; hence its denomination as "Cancer Integrin".^[1] Among them are the most lethal cancer varieties, such as pancreatic ductal adenocarcinoma (PDAC; 88% of cases are αvβ6-positive).^[2]

A high prevalence of αvβ6-integrin expression has furthermore been confirmed for other carcinomas, notably non-small-cell lung cancer (NSCLC; 97%), bladder cancer (TCC, 92%), esophageal squamous cell carcinoma (ESCC, 99%), as well as the female cancers endometrial- (EC, 92%), ovarian- (OVCa, 88%), and triple-negative breast carcinoma (TNBC; 89%) (see Image).

αvβ6-Integrin recognizing therapeutics and radioligands have great potential to selectively target and kill the respective tumor cells, while sparing healthy cells. Our goal is to use our proprietary peptides to drive the development of more effective cancer therapies with fewer side effects in order to improve the survival and quality of life of cancer patients.

[1] Quigley NQ, et al., Eur. J. Nucl. Med. Mol. Imaging 2022;49:1136.

[2] Steiger K, et al., Molecular Imaging 2017;16:1536012117709384.

The practical possiblity of selecting patients with disease-related, locally elevated αvβ6-integrin expression by using ⁶⁸Ga-Trivehexin^® as a selection biomarker opens an avenue to personalized therapy with highly disease-specific drug formulations (see Image). There is compelling evidence that αvβ6-integrin rapidly internalizes after binding to a ligand, such as a peptide.^[1] This mechanism is very robust and works well for peptides that have been equipped with anticancer drugs, such as cytotoxic agents.^[2,3]

The respective molecular constructs, often referred to as Peptide Drug Conjugates (PDCs, see Image), have the potential to actively transport the drug component they contain to and into the cancer cells. Such "magic bullets" can achieve higher drug concentrations in tumor tissue than their non-targeted siblings and thus enhance the anticancer effect of a drug. Furthermore, since the higher efficacy of such therapeutics may allow the total amount administered to be reduced, the treatment should be less toxic to αvβ6 integrin-negative healthy cells. PDC-based cancer therapies are therefore potentially more effective and have fewer side effects, with the prospect of improving the survival and quality of life of cancer patients.

World-leading scientists in the field have stated that "it is clear that specific targeting αvβ6 in humans is now a practical possibility and should become a platform for development of improved therapies for the effective treatment of pancreatic and hopefully many other types of cancer."^[3] Our goal is to unleash the therapeutic power of PDCs based on our proprietary αvβ6-integrin binding peptides.

[1] Meecham A, et al., Front. Cell Dev. Biol. 2022;10:920303.

[2] Ludwig BL, et al., Biomaterials 2021;271:120754.

[3] Moore KM, et al., Theranostics 2020;10:2930.

TRIMT's proprietary αvβ6-integrin targeting cyclopeptides can be equipped with a wide variety of other functional molecules. These so-called peptide conjugates may comprise fluorescent dyes that can be detected with fluorescence microscopes for cellular imaging. When such a compound is applied during a surgical procedure and surgeons use intraoperative fluorescence camera devices that allow them to better distinguish αvβ6-integrin expressing tumors from surrounding healthy tissue, this is called Fluorescence-Guided Surgery. In case the molecule contains a radioisotope that emits gamma-radiation and the intraoperative tumor detection is done with a handheld gamma probe, the procedure is called Radio-Guided Surgery.

The light-sensitive part of the peptide conjugate can also be a photocatalyst that releases cytotoxic substances (frequently, reactive oxygen species, ROS) when irradiated with light. In practice, such conjugates may be administered like the positron emission tomography (PET) tracer ⁶⁸Ga-Trivehexin^®. One they have reached their target, i.e., the αvβ6-integrin expressing tumor cells, the entire tumor area can be irradiated with high-intensity laser beams to selectively eradicate the tumor while spare the surrounding normal tissue. This concept is widely referred to as Photodynamic Therapy.

Our vision is to advance these emerging technologies for clinical cancer management by developing suitable innovative compounds based on our proprietary αvβ6 integrin-targeting peptides to offer new perspectives to cancer patients.

PD-L1 is the abbreviation for "Programmed cell Death Ligand 1", a cell surface protein that is recognized by the receptor PD-1 (Programmed Death receptor 1) of certain immune cells. Some cancer cells display PD-L1 in high concentrations on their surface to prevent an attack by the immune system (a so-called immune evasion mechanism).^[1] The clinical importance of PD-L1 arises from the fact that immune evasion can be reverted by anti-PD-L1 monoclonal antibodies (mABs) such as durvalumab, atelizumab, or avelumab, or by anti-PD-1 mAbs such as nivolumab or pembrolizumab. The immune system is thus re-enabled to recognize and eradicate the cancer cells. This form of cancer immunotherapy is referred to as checkpoint inhibitor therapy (recognized with the Nobel Prize in Physiology or Medicine, awarded 2018 to the PD-1 discoverer Tasuku Honjo).^[2]

Since PD-L1 is only expressed by a fraction of cancers, agents for clinical imaging of PD-L1 are of high interest to select those patients that are likely to benefit from said immunotherapies,^[3] or to monitor the progress of ongoing therapies.^[4]

TRIMT's portfolio includes tracers for positron emission tomography (PET) imaging of PD-L1, labeled with the short-lived medical isotope Gallium-68 (⁶⁸Ga). Preclinical imaging confirmed favorable properties for sensitive imaging of PD-L1 expression by PET (see Image).^[5]

[1] Ribas A, Wolchok JD. Science 2018;359:1350.

[2] https://en.wikipedia.org/wiki/Tasuku_Honjo

[3] Krutzek F, et al., Pharmaceuticals 2022;15:747.

[4] Nimmagadda S, Cancers 2020;12:3173.

[5] Notni J., et al., unpublished results.

αvβ8-Integrin is a potent modulator of the immune system and furthermore – like αvβ6-integrin – an activator of transforming growth factor β (TGFβ). As such, the expression level of αvβ8-Integrin in tissues is connected to a multitude of biological and pathological mechanisms involving TGFβ, including, but not limited to, cancer progression and metastasis.^[1]

TRIMT's αvβ8-Integrin targeted positron emission tomography (PET) tracer ⁶⁸Ga-Triveoctin was developed on the basis of a unique, highly selective octapeptide (see Image).^{[2] 68}Ga-Triveoctin is the first clinically relevant αvβ8-Integrin specific agent of this type.^[3] Potential applications include stratification of patients for αvβ8-Integrin-targeted therapies by non-invasive PET imaging.

[1] Takasaka N, et al., JCI Insight 2018;3:e122591.

[2] Reichart F, et al., J. Med. Chem. 2019;6:2024.

[3] Quigley NG, et al., EJNMMI Res. 2020;10:133.