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PinotBio – Targeting Relapsed/Refractory Cancer with well-designed multi-target agents

Cancer is still, in many cases, an incurable disease, despite many progresses for its treatment. Many anti-cancer therapeutics, including cytotoxic chemicals, targeted agents, immune-checkpoint inhibitors, and even CAR-T therapies, have been developed and raised positive anticipation. However, they have failed to fully overcome cancer. Initially, the therapeutic agents attack cancer cells very efficiently. However, cancer cells use their  amazing flexibility to adapt to evolutionary pressure. Cancer generates a small portion of cells that can survive the attack of anti-cancer treatments, resulting in relapsed/refractory cancer.

PinotBio, Inc., a South Korean-based clinical stage biotech, is seeking to treat those relapsed/refractory cancers by applying “well-designed multi-target anti-cancer treatments”. The novel anti-cancer therapeutics of PinotBio utilize well-known and well-established cancer treatment targets, such as DNA Methyltransferase 1 (DNMT1) and Topoisomerase 1. These therapeutics block one or more resistant pathways to overcome the development of resistance. As a result, PinotBio’s anti-cancer agents show stronger efficacy in various preclinical models and show the potential to overcome cancer resistance.

 

The development of anti-cancer therapeutics has evolved from poorly-defined, multi-targeted agents, so called “dirty chemicals”, to compounds targeting a well-defined pharmacological target existing in cancer cells or cells showing aberrant activities. The shortcomings of the previous approach were clear. The maximum tolerated dose of dirty chemicals was problematic. Due to the high toxicity, the chemicals could not be used sufficiently to kill all of the cancer cells in the patients –the remaining cancer cells developed various resistant mechanisms to combat the toxic anti-cancer agents. In the case of targeted agents, the smart cancer cells can develop clever ways to bypass the targeted pathway – if the EGFR signaling pathway is blocked, cancer cells rely on other receptors, such as Her2/FGFR, to bypass the signaling pathway. Thus, resistance could easily develop.

 

PinotBio attempts to overcome these problems by utilizing the novel concept of well-designed multi-target inhibition. In other words, PinotBio’s novel candidates are expected to show strong anti-cancer efficacy through the inhibition of well-established anti-cancer targets. At the same time, they target well-selected resistant mechanisms to show stronger efficacy and overcome resistance.

 

NTX-301, a leading clinical compound of PinotBio and a novel nucleoside DNMT1 inhibitor for the treatment of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), is a good example of this approach. MDS and AML are hematological malignancies, most prevalent in aged populations. Even though many innovative treatments have been developed, due to the physical conditions of aged MDS and AML patients, these novel approaches cannot be effectly used for elderly MDS/AML patients. Currently, their treatment is and will be highly dependent upon the use of DNMT1 inhibitors, such as Dacogen and Vidaza. The core issue is that after the failure of the first line treatment, there is no other treatment option for relapsed/refractory MDS/AML patients. There were many historical attempts to improve Dacogen and Vidaza, but none of them succeeded in overcoming the resistance problem.

 

PinotBio has succeed in developing the novel nucleoside DNMT1 inhibitor NTX-301 employing a thio-ribose backbone, which maintains potent DNMT1 inhibition and blocks resistance mechanisms against Dacogen and Vidaza. Most of the resistance against previous DNMT1 inhibitors originate from the upregulation of the anti-apoptotic signaling pathway, such as Bcl2 and/or the DNA-damage repair pathway. NTX-301 is equipped with the Azacytosine functional group, which confers potent DNMT1 inhibition. Together with a thio-ribose backbone, it can suppress the DNA damage repair pathway and overcome anti-apoptotic signaling pathway. Accordingly, NTX-301 possesses stronger efficacy than Dacogen/Vidaza against AML cells and has the potential to overcome Dacogen/Vidaza resistance. PinotBio has completed successful preclinical development of NTX-301, which is undergoing a phase I clinical trial at the University of Alabama, Birmingham.

 

PinotBio is also developing novel Antibody Drug Conjugates (ADCs) that employ novel a Camptothecin-based payload that can overcome previous ADC-resistance. ADCs are being targeted by many pharmaceutical companies as a next generation drug development platform. After the successful clinical development of Trodelvy, Enhertu, and Padcev, more and more companies are attempting to develop novel ADCs that can treat solid tumors. However, the problem of resistance, inevitably, follows, and new treatment options for the ADC-resistant patients are currently a highly unmet need.

 

The resistance toward any ADC therapeutics can occur from either antibody/linker-related resistance mechanisms or payload-dependent resistance mechanisms. A cancer cell can acquire resistance by changing the ADC trafficking after the antibody moiety binds to the cell surface. It can return the ADC back to the cell surface before the payloads are released, or it can block the entry of the ADC into the cell. Also, a cancer cell can over-express drug efflux transporters, which pump the payloads out of the cell, or over-express various anti-apoptotic pathways to avoid cell death.

PinotBio plans to avoid the resistance problems by using a novel payload. The antibody/linker related resistance can be overcome by adopting a drug linker that releases drugs very efficiently either in cancer cells or in the tumor microenvironment. For this purpose, the payload should be well-tolerated, even when it is released before entering tumor tissues, and after the release, it should easily diffuse into nearby cancer cells to show good by-stander effects. The payload-dependent resistance can be overcome by using a payload that is non-substrate to the drug efflux transporters and at the same time is able to suppress the expression of anti-apoptotic proteins.

The research team at PinotBio has searched for a novel, potent Camptothecin analogue that can satisfy all the criteria above. The new Camptothecin compound shows 10 times stronger tumor growth inhibition than SN-38, the payload for Trodelvy, against various solid tumor cell lines. Because the new Camptothecin is insensitive to the drug efflux pump, it maintains its efficacy even in cell lines resistant to SN-38 due to the over-expression of efflux pump. Also, after treatment with this new Camptothecin compound, the degradation of various anti-apoptotic proteins, including Survivin and XIAP, is observed in most solid tumor cells. This strong cellular efficacy translates well into animal model results - treatment with this new Camptothecin resulted in potent tumor growth inhibition, whereas SN-38 has shown virtually no efficacy at all. Furthermore, the compound is well tolerated in animal studies, enabling the employment of a novel linker system that releases the drug in both cancer cells and the tumor microenvironment. Based upon this new payload, PinotBio has secured the ADC platforms to produce ADCs with DAR 2, 4, or 8 in a site-specific manner. The resulting ADCs show stronger efficacy than previous ADCs targeting the same antigen.

 

“PinotBio is consistently trying to overcome the refractory/relapsed cancer. We all know that by targeting well-established cancer targets such as topoisomerase I, DNMT1, etc., we can achieve strong, initial therapeutic responses. The problem is how to suppress the development of resistance to maintain the initial responses. For this purpose, we will continue to pursue the approach of simultaneous targeting of well-established cancer targets and precisely chosen resistance pathways to achieve maximum effects” said Doo Young Jung, Ph.D., Founder/CEO of PinotBio.