Start with my personal story. After graduating from university, I became a doctor and was hired in a ward where many cancer patients were on beds. At the conference, the treatment method is decided, and the boss instructs me to administer anticancer drugs, etc., and I run around for examinations and medications. Some patients get progressively worse and die. Patients and families are praying with feelings that cannot be expressed in words. This blog is my perspective on cancer, inspired by the submission of the TNBC paper.

Statistical mining of triple-negative breast cancer-specific nanobodies among huge libraries from immunized alpacas | bioRxiv

Breast cancer can be classified into several types according to the expression patterns of human epidermal growth factor receptor 2 (Her2), oestrogen receptor (ER), and progesterone receptor (PgR) proteins. The prognosis of patients with tumors showing low Her2 expression and no ER and PgR expression—categorized as triple-negative breast cancer (TNBC)—is worst among these groups. Due to the lack of specific antibodies for TNBC, curative treatments for TNBC remain limited. Antibodies targeting TNBC have potential as diagnostic and therapeutic tools. Here, we generate a panel of nanobodies targeting TNBC cell lines by immunizing alpacas and subsequently panning the resulting phage libraries with TNBC cell lines. We show that several clones exclusively stain Her2-negative cells in tissues of breast cancer patients, and a few clones stain both Her2-positive and Her2-negative regions in these tissues. These clones can be applied to patient-specific therapies using drug-conjugated antibodies, radiolabelled antibodies, chimaera antigen receptor T cells, or drug delivery components, as well as to TNBC diagnosis. ### Competing Interest Statement The authors have declared no competing interest.

https://www.biorxiv.org/content/10.1101/2023.02.23.529685v1

There are many types of cancer

Depending on the organ, it is called lung cancer, stomach cancer, uterine cancer, and skin cancer, but there are subtypes for which no treatment has been established in each field. For example, small cell carcinoma accounts for about 10% of lung cancer. no definitive drug has been developed. In addition, 15% of breast cancers are triple-negative breast cancers, a group in which known biomarkers do not work. Then, MDs explain "There is no effective medicine and surgery is not possible, so spend meaningful time at home or in a hospice.”

Why no good drugs?

The biggest cause is that "the target molecule is unknown". Once we know the target molecule, we can use that molecule as a guide to developing treatments. The target molecule here refers to a biomarker for distinguishing "cancer cells" from healthy cells. For example, by developing an antibody that marks only "cancer cells" and injecting it with an anticancer drug, it is possible to eliminate only the target cells. However, drug discovery cannot even begin without knowing the target molecule. The most difficult thing for humans is to "find things that you don't know if they exist." It may not exist even if you invest a huge amount of effort and money into searching for it. Until now, the role of "searching for target molecules" has been entrusted to academia, but molecular medicine researchers tend to "focus on cells and molecules that are of interest to them," making it difficult to conduct comprehensive surveys. It has a difficult structure. This is because there is a tendency, as experts, to regard the results of academic societies in a rush to study specific molecules or cells in depth. Pharmaceutical companies are waiting for good information from universities, and researchers are following their own interests. Unfortunately, there is a gap between expectations and reality.

The second reason is economic demand. Depending on cancer, treatment methods have been established, and the survival rate (5-year survival rate) has increased. Cancers with unknown target molecules are increasingly becoming a minor category. As a result, the market size is small relative to the development costs, and large returns cannot be expected. There is an economic structure in which drug discovery cannot be started unless sales are expected to exceed 1 billion USD, which is a reason why pharmaceutical companies hesitate to develop new drugs.

Molecular Targeted Drug Discovery - What is Unmet Medical Needs?

Thank you for your patience with the long introduction. Over the past 40 years, efforts to find target molecules have borne fruit, and epoch-making drug discovery targets molecules such as Her2, EGFR, PD-1L, and OX40 have been discovered. Today, drug discovery engineering such as "ADC: antibody-drug-conjugate" and "CAR-T" are flourishing, and many of the blockbusters that are showing tremendous sales are "molecular-targeted drugs." In other words, it is an antibody-based drug that exerts its effect using the target molecule as a marker. Come to think of it, the impression that cancer is a disease that can be cured, a disease without fear of lethality, has become more ordinary than before. It can be said that this is largely due to the contribution of molecular-targeted drugs. On the other hand, there are still some cancers that progress quickly, and there are occasional news reports of young actors and actresses dying from pancreatic or bile duct cancers. They are a category for which there are no effective drugs, technically called Unmet Medical Needs.

Can't you find the target from the data?

COGNANO's work to search for unknown target molecules is like an explorer digging up a treasure after the total search. Unfortunately, the treasure may not even exist. Our bodies express hundreds of thousands kind of different molecules (to put it mildly) for proteins alone. The only system that can search for target molecules that (maybe) exist only in "cancer cells" on this scale is the antibody immune system of living organisms. At present, the huge computational power of antibody gene hypermutation in organisms cannot be reproduced either in vitro or in silico. The question is whether this comprehensive information can be deciphered by humans.

Search engines are constantly crawling the Internet, compiling and accumulating indexes. The end user accesses the search engine directly and retrieves information ordered by what appears to be useful.

The target molecule search system that COGNANO is aiming for imitates it. The natural immune system is a chaotic giant of information, theoretically having the potential (capacity) to recognize all biomolecules on Earth. Alpaca learns various cancer cells, extracts them as antibody gene information, and our IT team store them in the server. Since this database is electronic information, it will never be lost and will continue to grow. In addition, this database has a wide range of applications other than discovering cancer target molecules, and we plan to continue to publish mathematical papers in the future.

Imagine a sonic fish finder. If you have a good fisherman, a good fishing boat, and you know where your catch is, you should be able to increase your success rate. The radar that explores the entire ocean surface is the antibody immune system, and COGNANO's IT team translates the huge data set provided by nature so that it can be understood by humans. In the early days, it took many years for COGNANO to perform mathematical analysis from bio information, but now it has grown to the point where if you send it to the IT team, it will reply with the optimal solution. This time, we will release an overview of the technology, taking the discovery of biomarkers for triple-negative breast cancer as an example.

In order to solve unmet medical needs including rare cancers, COGNANO will create a database of antibody gene information and launch it at high speed. We entrust this result to the pharmaceutical industry and hope that it will reach the bedside of patients who are left behind as soon as possible.

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https://finance.yahoo.com/news/cognano-inc-statistical-discovery-triple-024500275.html

Alpaca antibody map against triple-negative breast cancer (TNBC) cell lines (left) and known breast cancer cell lines (right). Both are labelled by a most common group of antibodies (blue), but only a small group of antibodies (brown) can be found that bind specifically to TNBC. The odds are only a few hundred clones in a population of tens of millions of clones. Moreover, the hundreds of clones are aggregated into about 10 homologous groups (clusters). That is, it is estimated that there are several to ten types of TNBC target molecules of interest.

Looking back, though it's too early to win

Thirty years ago, I couldn't do anything. Currently, I notice alpaca must be the first computer, the IT program be the second computer. I know that it's beyond the realm of my intelligence. Delivering drugs to patients is another battle, in other words, it is a long road, including capital and approval. There are soaring walls that COGNANO alone cannot overcome. We have no choice but to wait for the support of everyone, including patients and people involved in pharmaceuticals. Hope you enjoy our article.