Company Profile

RIN Institute Inc.:

RIN Institute is a bio-venture established at the National Cancer Center Japan

Main Business Activities:

R&D of medicines and external diagnostic drugs based on monoclonal antibodies
1, Humanized anti-TMEM180 monoclonal antibody for treating several cancers, including colorectal cancer.
We created several monoclonal antibodies (mAbs) against new colorectal cancer (CRC)-specific molecules obtained after a comprehensive expression analysis of pure colorectal mucoepithelial cells and CRC cell lines.
One of these mAbs is anti-TMEM180, and Immunohistochemistry (IHC) showed 50%, 30%, and 30% positivity for CRC, breast cancer, and ovarian cancer, respectively.
As for the TMEM180 molecule, we found that its expression was enhanced under hypoxic conditions, but its biological function is currently under investigation. In normal tissues, we identified almost no expression of TMEM180 nucleic acids. IHC with a mAb we established showed almost no TMEM180 expression in normal tissues(1-2). The IHC also showed that high TMEM180 expression correlated significantly with poor overall survival (3).
The antitumor effect of the anti-TMEM180 antibody is exerted mainly via ADCC and ADCP. We confirmed a marked antitumor effect on colorectal cancer PDX, and obtained a significant antitumor effect even in a PDX characterized by KRAS mutations, in which anti-EGFR antibodies were ineffective.
GMP manufacturing and GLP toxicity tests were conducted based on the preclinical POC. Although the monkey TMEM180 gene is 97.7% homologous to that of humans, almost no toxicity was observed, even at a high dose of 100 mg/kg administered in a single injection.
A clinical trial notification was finally submitted in October 2022, and a phase 1 trial was started at the National Cancer Center in January 2023 and is progressing well.

2, Humanized anti-insoluble fibrin (IF) Ab-MMAE conjugate for the treatment of invasive tumors.
In 1986, Matsumura and the late Prof. Maeda of the Kumamoto University School of Medicine published a paper on the enhanced permeability and retention (EPR) effect as a theoretical pillar of high-molecular-weight drug delivery systems, including antibody therapeutics (4). EPR effects have been globally proven in studies using mouse tumor models, and thanks to these studies, Matsumura and Maeda were awarded the Thomson Reuters Award in 2016. However, the phenomenon has not been clearly demonstrated clinically in human solid tumors, and has thus not been fully accepted in clinical fields. Matsumura noticed that macromolecules do not adequately reach deep regions of human solid tumors due to the cancer stroma functioning as an interstitial barrier. He therefore decided to establish mAbs against several components of the cancer stroma, and in January 2006 he succeeded in creating a mAb against IF, a pathological substance in the interstitial barrier.
This anti-IF antibody, unlike previously generated ones, only recognizes IF and does not bind to water-soluble fibrinogen, fibrin monomer, or FDP. The epitope amino acids are completely conserved from fish to humans, and experimental results in mice and monkeys can be extrapolated to humans (5).
In 2011, Yasunaga M, Manabe S, and Matsumura Y published a study on the first cancer stromal targeting (CAST) therapy using the anti-IF antibody conjugated with the anticancer agent MMAE. This therapy aims to overcome the insufficiency of the EPR effect in human solid tumors which possess abundant stromal tissue. MMAE was bound to the IF mAb via a Val-Leu-Lys linker peptide that is specifically cleaved by plasmin. This ADC accumulates in the cancer stroma due to the EPR effect. It then binds to IF, and the MMAE is released only by plasmin activated on IF within the cancer stroma. The released MMAE is evenly distributed in the cancer tissue, where it effectively damages cancer cells, and it also acts on tumor blood vessels (6-8). The authors also demonstrated that plasmin is completely neutralized by in vivo plasmin inhibitors except on IF, and that release of the anticancer drug from the ADC occurs only on IF in the cancer stroma (8). This linker is therefore very stable in the bloodstream, which means that minimal toxicity can be expected. Furthermore, the authors established new anti-IF mAbs, selected the clone with the highest affinity and specificity, and determined the final dosage form of the ADC (9). In addition, Matsumura's team confirmed that the administration of the ADC did not cause tissue damage or hemorrhaging, even at thrombin-formed thrombus sites in mice models. Based on these results, RIN Institute has started preclinical development, including the research process for GMP production of the anti-IF-MMAE ADC, in order to enter a phase 1 trial in 3 years.

3, Fusion protein of the Fab of anti-IF antibody and mutated urokinase for the treatment of acute cerebral infarction.
The fusion protein of the Fab of anti-IF antibody can selectively deliver a thrombolytic agent to a thrombus (10). The selling points of this antibody-thrombolytic agent fusion (AT fusion) molecule include the following:
1) By achieving selective delivery to the thrombus, the thrombolytic effect can be enhanced.
2) There is no single-chain activation that can prolong the half-life in blood, resulting in less systemic toxicity.
3) There is less injury to tissue around the thrombus because the AT fusion molecule cannot bind urokinase receptors surrounding the thrombosis, and MMPs around the thrombus are not activated.
4, Other pipelines
1) Anti-TMEM132A mAb conjugated with MMAE
TMEM132A is a cancer-specific membrane protein discovered at the same time as TMEM180, and an ADC was produced after humanizing the mAb.
2) Bispecific antibody comprised of an anti-TMEM180 antibody and an anti-CD3 antibody
3) Anti-tissue factor mAb conjugated with MMAE

References:

1) Yasunaga M et al. Significant antitumor effect of an antibody against TMEM180, a new colorectal cancer-specific molecule. Cancer Sci. 2019;110(2):761-770.
2) Anzai T, Matsumura Y. Topological analysis of TMEM180, a newly identified membrane protein that is highly expressed in colorectal cancer cells. BiochemBiophys Res Commun. 2019;520(3):566-572.
3) Shiraishi Tet al. High expression of TMEM180, a novel tumour marker, is associated with poor survival in stage III colorectal cancer.
BMC Cancer. 2021 Mar 23;21(1):302.
4) Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46:6387-6392.
5) Hisada Yet al. Discovery of an uncovered region in fibrin clots and its clinical significance. Sci Rep. 2013;3:2604.
6) Yasunaga M, Manabe S, Matsumura Y. New concept of cytotoxic immunoconjugate therapy targeting cancer-induced fibrin clots. Cancer Sci. 2011;102(7):1396-1402.
7) Matsumura Y. Cancer stromal targeting (CAST) therapy. Adv Drug Deliv Rev. 2012;64(8):710-719.
8) Fuchigami H et al. Chemotherapy payload of anti-insoluble fibrin antibody-drug conjugate is released specifically upon binding to fibrin. Sci Rep. 2018;8(1):14211.
9) Fuchigami H, Matsumura Y. Characterization of antibody clones that bind exclusively to insoluble fibrin. 2023; 34(1):20-27
10) Hanaoka S, Saijou S, Matsumura Y. A novel and potent thrombolytic fusion protein consisting of anti-insoluble fibrin antibody and mutated urokinase. ThrombHaemos 2021 122: 57-66

What's RIN?

The company name "RIN " is the abbreviation for "Robust Immuno-diagnosis and therapy against malignant Neoplasm."

Company Name RIN Institute Inc.
Date founded January 21,2016
Company Address 1-13-10-2F Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan
President Masaaki Fujiwara