A Road to Conquering Cancer — Successful Development of Antibody Drug as Potential Cure for Difficult-to-Treat Cancer

관리자 │ 2018-02-13



- Drastic tumor reduction rate of 85% in the preclinical studies in animals... STCube moves forward with its plan for global licensing out


The novel antibody drug developed by a domestic company was reported to show drastic effects on difficult-to-treat cancers. In particular, the new antibody is reported to show excellent efficacies on triple negative breast cancer and colon cancer with poor prognostic results, while showing significantly reduced side effects, providing a step forward to conquering cancer.


STCube reported that the company had decoded the functions of glycosylation on immune-checkpoint protein PD-L1, and the research findings on the development of PD-L1 antibodies based on this new concept and efficacies of those antibodies have been published in the online version of Cancer Cell (Impact Factor: 27.407), a globally respected cancer research journal  (Paper name: Eradication of triple negative breast cancer cells by targeting glycosylated PD-L1).


Noting that glycosylation occurred on the PD-L1 protein in difficult-to-treat cancers with poor prognositc results such as triple negative breast cancer, the company conducted research on glycosylated PD-L1 in collaboration with MD Anderson Cancer Center. In order to validate the applicability of research findings in clinical settings, antibodies that selectively mask glycosylation moieties on PD-L1 were developed, and improved anti-cancer efficacies associated with those antibodies were also uncovered.


It was also reported that some of the novel antibodies developed by STCube not only neutralize the binding of PD-1/PD-L1 that interferes with the immune reactions to tumor cells, but also internalize and degrade PD-L1 protein.


Particularly, STCube antibodies are reported to possess optimum characteristics to produce antibody-drug conjugates based on this internalization function. When the efficacies of the glycosylation-specific antibody-drug conjugate (gPD-L1-ADC) were investigated, bystander effect where adjacent cancer cells with no antibody binding perish together with cancer cells with antibody binding.


In preclinical animal testings, it was shown that tumors drastically decrease upon treatment by the company’s antibodies, showing response rate as high as 71 to 86%. Since the antibodies showed no significant side effects on kidney or liver functions, production of glyco-specific antibodies is expected to make significant contribution in development strategies for cancer treatment.


According to a company official, "[W]e are pleased to note that STCube researchers were named as co-authors on the article in Cancer Cell, one of the world-best cancer research journals, the article being the first from Korea on immune-checkpoint protein PD-L1. As this is a study conducted with commercialization in sight, the company plans to move forward with steps to commercialize the drug, for example, through collaborations with multinational pharmaceutical companies.


T-cells, immune cells present in our body, attack abnormal cells when detected. The problem is, though, cancer cells adopt various defense mechanism to avoid immune attacks from T cells in order to survive. For example, Cancer cells produce PD-L1 protein as a defensive mechanism. As PD-L1 protein on the surface of cancer cells binds to PD-1 protein in T cells, T cells lose their ability to attack cancer cells. Some of the recent anti-cancer immunotherapeutic agents regarded as next-generation cancer therapies are based on preventing binding of PD-1/PD-L1 protein and resulting disablement of T cells.


At present, however, although antibodies preventing binding of PD-L1 and PD-1 are available, their response rate is in the range of 15 to 30%. Further, relatively high incidence of autoimmune disorders such as Crohn’s disease and lupus is being reported among patients who receive the antibodies. Therefore, a need for alternative ways to improve the efficacy and safety of PD-1/PD-L1 blockade has been recognized.


Unlike existing PD-1/PD-L1 therapies, the antibody developed by STCube can be less toxic and more efficacious since the biomarker may be set up on the basis of PD-L1 glycosylation. In addition, the company believes that the novel antibody-drug conjugate (gPD-L1-ADC) has the potential to expand the horizon of immune-checkpoint inhibitors.


One official of STCube stated: “Because there are no approved ADC-based PD-L1 therapy, if this product is developed successfully, it will be the first antibody-drug conjugate utilizing immune-checkpoint antibodies. The antibody-drug conjugate that has been developed by STCube can provide an innovative target therapy that can be used in clinics."


According to GBI Health, a global market survey agency, the anti-cancer immunotherapy market has been expanded at the rate of 23.9% each year, and in 2025, it will increase up to the level of USD 75.8 billion (about 90 trillion won). <End>




# What Is Glycosylation? = A form of post-translational modification (PTM) after protein synthesis by which sugar moieties get linked to proteins. It provides various functions to proteins such as effects on protein-protein interactions, protein folding, and transport. STCube researchers have published a report on the research finding that PTM-based glycosylation on PD-L1 stabilizes PD-L1 and regulates activation of T cells. Hence, glycosylation on PD-L1 can be utilized as a biomarker in clinical settings, or in developing combination treatment.


# PD-L1 protein = PD-L1 is found in cancer cells, macrophages, dendritic cells, matrix cells, etc. When PD-L1 binds to PD-1 on the surface of T cells, cancer cells can escape from immunological surveillance by T cells. PD-L1 antibodies currently available have shown significant clinical effects in activating tumor infiltrating lymphocyte. However, the response rate remains low around 15-30%, and side effects such as autoimmune disorders (Crohn's disease and lupus) are reported to occur.


# Research background = patients with triple negative breast cancer (TNBC)

TNBC is the most aggressive form among breast cancers (highly-differentiated, progressive, and recurrent), but there is no efficient therapy or treatment strategy due to the lack of evident target for treatment (HER2, Hormone). In general, therefore, treatment is performed according to the empirical decision of clinicians, and the therapeutic effect is insignificant. As the effect of immune-checkpoint inhibitors is also insignificant, the response rate in Keynote012 clinical trials was 18.5% and that in Keynote086 clinical trials was 5%. In a recent report announced at AACR in April 2017, it was reported that in the 1b-phase clinical trial for atezolizumab, the response rate was 26%.


# Development of ADC to verify roles and production paths of glycosylated PD-L1 protein and for use in clinics

STCube research team, in one of its papers, presented roles of glycosylated PD-L1 protein. According to this article, glycosylation on PD-L1 plays an important role in inhibiting immune reactions because it is essential for PD-1/PD-L1 binding. Hence, STCube research team has developed antibodies that preferentially bind to glycosylated PD-L1 for clinical uses.

PD-L1 has 4 glycosylation sites, and antibodies exhibit different characteristics depending on the specific glycosylation sites that they mask. Further, it was found that some antibodies developed by STCube research team internalize and degrade PD-L1 protein, in addition to neutralizing the PD-1/PD-L1 binding. Accordingly, antibody drug conjugates were produced by adding therapeutic agents to these antibodies.

It is known that glycosylated PD-L1 is expressed in antigen presenting cells which are believed to contribute to the inhibition of immune functions. According to the company’s experimental results, normal tissues and immunocytes of peripheral blood showed low expression of PD-L1 and glycosylated PD-L1, while myeloid DC and tumor associated macrophage showed glycoslated PD-L1 expression, possibly providing ways to induce cell-specific death.


# Glycosylated PD-L1-ADC treatment shows a significant efficacy and safety

In the breast cancer mouse models designed to test the efficacy of the glycosylation-specific antibody-drug conjugate (gPD-L1-ADC), cancer cells disappeared from 6 out of 7 mice as the gPD-L1-ADC was shown to have high affinity to cancer cells. Also in colon cancer mouse models, cancer cells disappeared from 5 out of 7 mice. As cancer cells with antibodies bound perished, bystander effect, where adjacent cancer cells with no antibody bound also perished, was observed. Besides, there was no detectable side effect shown on the kidney or liver.


# Expected effects = gPD-L1-ADC has been developed and is at a stage for further clinical application. As antibodies more specific to cancer cells with poor prognosis such as triple negative breast cancer have been identified, a novel direction for anticancer therapy development that improves on the efficacy of antibody-drug conjugates, while reducing the side effects, has been laid out.


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