On January 7, 2020 Hummingbird Bioscience, an innovative biotherapeutics company pioneering the discovery and development of new breakthrough precision antibody therapeutics for difficult-to-treat conditions, reported the publication of preclinical data for its lead candidate, HMBD-001, an anti-HER3 antibody, in Molecular Cancer Therapeutics, a high-impact peer-reviewed American Association of Cancer Research journal (Press release, Hummingbird Bioscience, JAN 7, 2020, View Source [SID1234552813]).

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HMBD-001 is a unique anti-HER3 antibody with a novel mechanism of action and favorable safety profile. HER3 is a member of the EGFR tyrosine kinase receptor family, which is responsible for driving cancer cell division and growth, and is expressed in over half of colorectal and gastric cancers, at least a third of breast cancers, as well as significant sub-populations of many other indications.[1] HER3 activation is implicated in cancer progression as well as in acquired resistance to drugs against other tyrosine kinase receptor family members such as EGFR (e.g. cetuximab or Erbitux) and HER2 (e.g. trastuzumab or Herceptin). HMBD-001 was developed using Hummingbird Bioscience’s proprietary Rational Antibody Discovery Platform to specifically bind to and inhibit a difficult-to-access region of the HER3 protein that is essential for activation.

The published findings show that HMBD-001 (also known as 10D1F) is superior at tumor growth inhibition, regardless of how HER3 is activated, compared to previous anti-HER3 drugs with different binding sites and mechanisms of action. HMBD-001 demonstrated potent efficacy in a broad panel of in vitro and in vivo tumor models that had high HER3 activity and oncogenic downstream signaling.

"Previous attempts to target HER3 with other drugs failed as they could not inhibit activation of HER3 effectively. The highly specific binding of HMBD-001 to a difficult-to-target region on HER3 allows us to completely shut off activation of this important cancer-associated protein," said Dr Jerome Boyd-Kirkup, Chief Scientific Officer and co-founder, Hummingbird Bioscience. "This preclinical data provides proof-of-concept and represents exciting therapeutic opportunities for us as we look to develop HMBD-001 in hard-to-treat conditions such as gastric, colorectal, lung and pancreatic cancers."

Hummingbird Bioscience, in partnership with Cancer Research UK, will be advancing HMBD-001 into clinical trials for the treatment of HER3 driven cancers. Manufacturing of the material for the Phase 1 clinical trial of HMBD-001 is underway and is expected to be completed in the second half of 2020.

The paper titled 10D1F, An Anti-HER3 Antibody that Uniquely Blocks the Receptor Dimerization Interface, Potently Inhibits Tumor Growth Across a Broad Panel of Tumor Models can also be accessed online at View Source

About HMBD-001

HMBD-001 represents a unique, highly-specific, anti-HER3 neutralizing antibody with a novel mechanism of action that offers significant potential for broad clinical benefit. Previous attempts to block the HER3 receptor, a key player in the signaling pathway that promotes cell division and tumor growth in cancer, have not proven to be efficacious. HER3 is activated by the binding of neuregulin (NRG1), which stabilizes a transient open conformation to allow it to form heterodimers with HER2/EGFR. In the presence of abundant HER2/EGFR, heterodimers can form without NRG1.

Preclinical models have shown that HMBD-001 is able to effectively and uniquely bind to a
difficult-to-target region on HER3, blocking the heterodimerization of HER3 with HER2/EGFR independent of NRG1 binding. This potently inhibits the activation of the signaling pathway – and consequently, stops tumor growth.

Cancer Research UK has partnered with Hummingbird Bioscience to advance this novel antibody drug into clinical trials for the treatment of HER3 driven cancers. The clinical trial of this investigational candidate is expected to commence following the completion of manufacturing and the subsequent submission of regulatory approval.

On January 7, 2020 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) reported how resistance to a promising targeted drug develops in patients with a rare, lethal cancer of the bile ducts called cholangiocarcinoma (Press release, The Ohio State University Comprehensive Cancer Center, JAN 7, 2020, View Source [SID1234553217]).

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The study, reported in the journal Molecular Cancer Therapeutics, also suggests that adding another drug at the time of progression might re-sensitize tumor cells to the initial drug, called an FGFR inhibitor.

"While the majority of patients with FGFR-positive cholangiocarcinoma benefit from new FGFR inhibitors in clinical trials, most patients unfortunately develop cancers resistant to the drugs," says study leader Sameek Roychowdhury, MD, PhD, a medical oncologist and researcher at the OSUCCC – James. "We believe that this study is an important step in understanding drug resistance and improving the treatment of this and other cancers caused by abnormal FGFR gene mutations."

Findings also suggest that monitoring fragments of circulating tumor DNA for acquired mutations that cause resistance to FGFR inhibitors may reveal the presence of resistance mutations and mark the time a patient should begin taking the additional drug, an mTOR inhibitor.

The successful treatment of cholangiocarcinoma is challenging because the disease is usually diagnosed at an advanced stage that has a five-year survival rate of 2%. Patients diagnosed earlier also have low, five-year survival due to high rates of disease recurrence. Abnormal activation of the FGFR gene happens in 15 to 20% of people with cholangiocarcinoma, and FGFR inhibitors show effectiveness in 70 to 80% of those patients until resistance develops. There are six studies of FGFR inhibitors in clinical trials at the OSUCCC – James.

"A better understanding of how treatment resistance develops and how to prevent it is critical for improving the treatment of cholangiocarcinoma and other cancers caused by FGFR mutations," says first author Melanie Krook, PhD, a postdoctoral fellow in Roychowdhury’s lab.

"Our findings suggest that cholangiocarcinoma patients treated with an FGFR targeted therapy could potentially benefit from combination therapies with other drugs such as mTOR inhibitors. Additional laboratory studies are needed to identify the optimal lead strategies for this combination," she adds.

For this study, Roychowdhury, Krook and colleagues examined the FGFR (fibroblast growth factor receptor) gene in the cancer cells of a cholangiocarcinoma patient who died after experiencing disease progression and developing resistance to the FGFR inhibitor infigratinib.

The researchers identified two acquired FGFR mutations in the patient’s tumor cells that conferred resistance to FGFR inhibitors. They then used cancer cell lines to learn that the mutations led to activation of the mTOR biochemical pathway. This enabled the cancer cells to grow even in the presence of FGFR inhibitors. Adding an mTOR inhibitor to the cells restored their sensitivity to FGFR inhibitors.

Key findings:

Two acquired FGFR2 mutations, p.E565A and p.L617M, were shown to drive resistance to the FGFR inhibitor infigratinib.

The p.E565A mutation upregulates the mTOR signaling pathway, which desensitizes cholangiocarcinoma cell lines to infigratinib and other FGFR inhibitors.

A drug that inhibited the mTOR pathway restored the sensitivity of the cells to infigratinib and other FGFR inhibitors.

"Overall, our findings suggest that an mTOR inhibitor administered at the time of progression may re-sensitize tumor cells to an FGFR inhibitor in patients who develop resistance to these agents," Roychowdhury says.

This study was supported by grants from the American Cancer Society (MRSG-12-194-01-TBG), the Prostate Cancer Foundation, the National Institutes of Health (HG006508, CA202971, CA216432), the American Lung Association and Pelotonia.

Other researchers involved in this study were Alexandria Lenyo, Max Wilberding, Hannah Barker, Mikayla Dantuono, Hui-Zi Chen, Julie W. Reeser, Michele R. Wing, Jharna Miya, Eric Samorodnitsky, Amy M. Smith, Thuy Dao, Dorrelyn M. Martin, John L. Hays and Aharon G. Freud, The Ohio State University; Kelly M. Bailey, University of Pittsburgh; and Kristen K. Ciombor, Vanderbilt University.

On January 7, 2020 Advaxis, Inc. (Nasdaq: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products, reported the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application for the initiation of a Phase 1 clinical study of ADXS-504, the Company’s ADXS-HOT candidate for prostate cancer (Press release, Advaxis, JAN 7, 2020, View Source [SID1234552779]). ADXS-HOT is the Company’s off-the-shelf neoantigen clinical program targeting hotspot mutations that currently includes over ten cancer-type specific drug constructs in various stages of development.

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"With encouraging proof-of-concept data within our neoantigen program, we believe the ADXS-HOT program has potential to provide off-the-shelf, neoantigen targeted immunotherapies to a broad patient population," said Kenneth A. Berlin, President and Chief Executive Officer of Advaxis. "We are proud of the progress we have made to date with our HOT program, which includes advancing the clinical development of ADXS-503, our candidate for non-small cell lung cancer, while also seeking to launch our next clinical program, ADXS-504, in prostate cancer. We look forward to presenting immunogenicity and safety data from the first cohort from our lung program later this quarter."

On January 7, 2020 Y-mAbs Therapeutics, Inc. (the "Company" or "Y-mAbs") (Nasdaq:YMAB), a late-stage clinical biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, reported that Dr. Claus Møller, MD, Ph.D., Chief Executive Officer of Y-mAbs Therapeutics will provide an overview and update on the company’s business at the 38th Annual J.P. Morgan Healthcare Conference in San Francisco, California (Press release, Y-mAbs Therapeutics, JAN 7, 2020, View Source [SID1234552796]). The presentation will take place on Wednesday, January 15, 2020, at 4:30 PM Pacific Standard Time. The presentation can be accessed via a live webcast.

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On January 7, 2020 Sirnaomics Inc. ("Sirnaomics"), a leading biopharmaceutical company in discovery and development of RNAi therapeutics against cancer and fibrotic diseases, and Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops and commercializes high quality medicines for the treatment of oncology, autoimmune, metabolic and other major diseases, jointly reported that the two companies have entered a strategic collaboration to conduct clinical studies, using Sirnaomics’ RNAi drug candidate STP705 (cotsiranib) and Innovent’s antibody drug Tyvyt (sintilimab injection), for combination treatment in advanced cancers, such as Hepatocellular Carcinomas (HCC) and Cholangiocarcinoma (CCA), with high unmet need in the US (Press release, Sirnaomics, JAN 7, 2020, View Source [SID1234552814]).

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Patrick Lu, PhD, President and Chief Executive Officer of Sirnaomics, stated, "This collaborative effort between Sirnaomics and Innovent will be the first example of a combination strategy using an RNAi drug candidate together with an approved immune checkpoint antibody drug for the treatment of liver cancers. This represents an important clinical approach for combating these deadly diseases where the silencing of gene targets that reduce T-cell access and activity may augment the activity of checkpoint inhibitors in liver cancer."

Michael Molyneaux, MD, Chief Medical Officer of Sirnaomics, stated, "Sirnaomics is very excited to enter into this collaboration agreement with Innovent to potentially bring lifesaving therapies to patients with Hepatocellular Cancers. It is well known that, despite recent advances in cancer therapies, HCC is still a deadly form of liver cancer with high unmet need. Our pre-clinical Proof of Concept oncology data has consistently demonstrated single agent efficacy with STP705 in HCC and our most recent work on mechanism of action strongly suggest that the use of our lead asset (STP705) in combination with antibody therapies could greatly benefit patients with HCC. Innovent has a very strong track record for innovation and execution in the clinical space and a shared vision of bringing lifesaving therapies to their patients. We believe that combining Sirnaomics novel siRNA technology with Innovent’s cutting edge antibody therapies has the potential to significantly improve the current treatment landscape for patients with Hepatocellular Cancer."

Dr. Hui Zhou, Vice President and Head of Oncology Strategy and Medical Sciences of Innovent, stated, "Sintilimab has been granted marketing approval by the NMPA and is the only PD-1 inhibitor included in the NRDL. Sintilimab has gained broad recognition by the market, due to its profiles in safety and efficacy. Through partnership with other companies, we are exploring more sintilimab-based combination therapies and have seen some promising results. Developing a combination therapy, comprised of an antibody drug and a RNAi drug, may provide more comprehensive and effective treatments for patients. The potential clinical value of the combination therapy of sintilimab and cotsiranib will be evaluated and we hope more patients will benefit from this potential therapy globally."

About STP705 (Cotsiranib)
Sirnaomics’ leading product candidate, STP705, is an siRNA (small interfering RNA) therapeutic which takes advantage of a dual-targeted inhibitory property and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expression. The product candidate has received multiple IND approvals from both the US FDA and Chinese NMPA, including treatments of Cholangiocarcinoma, Non-Melanoma skin cancer and Hypertrophic Scar. STP705 has also received Orphan Drug Designation for treatment of Cholangiocarcinoma and Primary Sclerosing Cholangitis. STP705 has demonstrated a dramatic improvement in T-cell penetration into tumors in the liver with single agent action as well as improvement in the efficacy of an anti-PD-L1 antibody checkpoint inhibitor in an HCC model. This effect may improve other immune checkpoint inhibitor efficacies in addition to those targeting the PD-1/PD-L1 axis.

About Tyvyt (Sintilimab Injection)
Tyvyt (sintilimab injection), an innovative drug jointly developed in China by Innovent and Lilly, was granted marketing approval by the NMPA for r/r cHL in 2018, and included in the 2019 Guidelines of Chinese Society of Clinical Oncology ("CSCO") for Lymphoid Malignancies. Tyvyt (sintilimab injection) has been the only anti-PD-1 monoclonal antibody included in the NRDL since 2019.

Tyvyt (sintilimab injection) is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1/ PD-1 Ligand-1 (PD-L1) pathway and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies for sintilimab injection to evaluate its safety and efficacy in a wide variety of cancer indications, including eight registration or pivotal clinical trials. Innovent is also conducting clinical studies of sintilimab injection in the United States.