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SPOTLIGHTS
Precision Medicine using Innovative Biotherapeutics
In early January 2020, Hummingbird Bioscience published preclinical data showcasing the efficacy of its anti-HER3 antibody known as HMBD-001 (also known as 10D1F.1) The findings demonstrate the capabilities of Hummingbird Bioscience as an innovative biotherapeutics company to deliver precision medicine for challenging medical conditions.

HER3 belongs to a family of receptors known as Human Epidermal Growth Factor Receptor. It is well known that these receptors are abnormally turned on in multiple cancers and are associated with pathogenesis and disease progression, as such led to many potential drug targets which include HER3.

Despite its low level of expression in tumours, its association in signalling pathways for cell proliferation and tumour growth has garnered interest for it as a therapeutic target. Its ability to form a heterodimer with EGFR or HER2 to activate a cell signalling pathway indicates it crucial role in tumour progression.2

In the preclinical data published by Hummingbird Bioscience1 on Molecular Cancer Therapeutics it highlights the efficacy of the company’s novel anti-HER3 antibody, HMBD-001 in blocking heterodimerization to inhibit tumour growth.

The discovery of new ways to develop antibody therapeutics lays down the premise of Hummingbird Bioscience in formulating solutions for precision. APBN had the privilege to pick the brain of Dr Jerome Boyd-Kirkup, Chief Scientific Officer of Hummingbird Bioscience to deep dive into the innovations and focus of the company in achieving its goal of engineering new biotherapeutics for precision medicine.

1. What does precision medicine mean to Hummingbird Bioscience?

Precision medicine means getting the right treatment to the right patient at the right time. Hummingbird is dedicated to leading the future of precision biotherapeutics discovery and development. Specifically, and importantly, this means precisely identifying key target proteins in a disease, understanding the most effective therapeutic strategy to address that protein, and then developing the most powerful biotherapeutic that hits the optimal place on the protein to achieve the desired clinical outcome.

2. Can you explain Hummingbird’s business and drug development model?

Hummingbird was founded to address a need for new approaches to biotherapeutic discovery and development that would leverage the latest advances in combining powerful computational analysis with cutting-edge biology to build new therapies for patients with difficult-to-treat conditions.

Currently, discovery models have been inefficient as they rely heavily on trial and error testing; we are upending convention with our proprietary data and systems biology-based integrative approach that engineers the best possible biotherapeutic against key disease targets.

We focus on important and challenging targets with strong biological validation and disease association in well-defined populations. Enabled by our proprietary Rational Antibody Discovery platform, we rapidly pursue drug discovery programs where there is a clear line of sight to clinical proof of concept.

Our deep pipeline of novel programs is either first-in-class or have highly differentiated mechanisms that offer the potential for best-in-class efficacy in various indications, including oncology, CNS, and immunology. This includes two of our lead investigational assets, HMBD-001 and HMBD-002, which we are advancing into the clinic with partners such as Cancer Research UK and CPRIT in Texas. In addition, we have partnered with Amgen to co-discover and develop new biotherapeutics against multiple undisclosed targets in a broad range of diseases.

3. What are the disease areas that Hummingbird Bioscience will be focusing on especially for the Phase 1 clinical trial of HMBD-001 and why?

HMBD-001 is a unique antibody being investigated in HER3 driven cancers. HER3 is a well characterized disease-associated signal protein that has been shown to be responsible for driving cancer cell division and growth. It 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.a It is also implicated in cancer progression as well as in acquired resistance to drugs against other tyrosine kinase receptor family members such as EGFR and HER2. However, previous attempts to effectively block its activation have been unsuccessful due to the difficulty of addressing the different routes by which the protein becomes activated. Using our rational approach, we have been able to precisely design and engineer an antibody that can bind to a key hard-to-reach region on the HER3 protein and thus completely block all mechanisms of activation.

We plan to advance HMBD-001 into the clinic in gastric cancer, colorectal cancer, and an increasingly important genetically defined population known as NRG1 fusion, which is present in one to two percent of many cancer types including lung and pancreatic cancer. These are areas of significant need as current therapies often fail patients.

4. Could you share what is the mechanism of action of HMBD-001 in targeting HER3?

Previous attempts to turn off the HER3 receptor, a key player in the signalling pathway that promotes cell division and tumour growth in cancer, have been unable to block the different ways the protein can become activated. HER3 can be activated by the binding of the ligand, neuregulin (NRG), which stabilizes a form of the protein that enables it to form heterodimers with HER2/EGFR. However, heterodimerization can also occur without NRG, when there is an abundant presence of HER2/EGFR, as in the case of many cancers.

Our data has 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 NRG binding. This allows us to completely block the activation of the downstream signalling pathway, turn off the signal for the cancer cell to grow and consequently stop tumour growth in its tracks.

5. In the future, what format of drug delivery does Hummingbird Bioscience hope to achieve for its antibody therapies?

We are always on the lookout for new technologies to make drug delivery easier and safer for patients. At the moment, as biotherapeutics are large proteins that are difficult to be absorbed in the digestive system, we expect that our drugs will be delivered by injection or IV infusion. We test formulations and storage vessels, during the manufacture of the drug, that will allow it to stay stable while it is shipped around the world to patients. This can be liquid that is kept refrigerated or freeze-dried powder that can be shipped at room temperature before being dissolved in the doctor’s clinic prior to administration.

References

  1. Thakkar, D., Sancenon, V., Taguiam, M. M., Guan, S., Wu, Z., Ng, E., Paszkiewicz, K. H., Ingram, P. J., & Boyd-Kirkup, J. D. (2020). 10D1F, an Anti-HER3 Antibody that Uniquely Blocks the Receptor Heterodimerization Interface, Potently Inhibits Tumor Growth Across a Broad Panel of Tumor Models. Molecular Cancer Therapeutics. https://doi.org/10.1158/1535-7163.MCT-19-0515
  2. Mishra, R., Patel, H., Alanazi, S., Yuan, L., & Garrett, J. T. (2018). HER3 signaling and targeted therapy in cancer. Oncology reviews, 12(1), 355. https://doi.org/10.4081/oncol.2018.355

Footnote

  1. Li, Q., Zhang, R., Yan, H., Zhao, P., Wu, L., Wang, H., Li, T., & Cao, B. (2017). Prognostic significance of HER3 in patients with malignant solid tumors. Oncotarget, 8(40), 67140–67151. https://doi.org/10.18632/oncotarget.18007

About the Interviewee

Dr Jerome Boyd-Kirkup is the Co-founder and Chief Scientific Officer of Hummingbird Bioscience, an innovative biotechnology company that is pioneering the discovery of breakthrough therapies for difficult-to-treat indications. He is responsible for overseeing the development of new technologies and intellectual property, designing experimental strategies for drug discovery, leading the development and testing of novel therapeutics, and overseeing the drug pipeline. Prior to co-founding Hummingbird, Dr Boyd-Kirkup was an academic at top institutions in the UK and China. He holds a Bachelor's and Master's degree in Biochemistry from Imperial College London and a PhD in Molecular Biology from Cambridge University.

Hummingbird was founded in 2015 and has built a world-class team of 30 staff in Singapore, supported by a deeply experienced international board and scientific advisory panel including James P Allison, winner of the 2018 Nobel Prize for Medicine. To date, Hummingbird has raised more than USD $60 million, which has fueled the development of a pipeline of exciting new antibody drugs. Human trials of the first two anti-cancer drugs are scheduled for 2020.

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