Axial partners with great founders and inventors. We invest in early-stage life sciences companies such as Appia Bio, Seranova Bio, Delix Therapeutics, Simcha Therapeutics, among others often when they are no more than an idea. We are fanatical about helping the rare inventor who is compelled to build their own enduring business. If you or someone you know has a great idea or company in life sciences, Axial would be excited to get to know you and possibly invest in your vision and company . We are excited to be in business with you - email us at info@axialvc.com
Inventors #3
A set of ideas and observations on inventions and discoveries in life sciences.
Immunology
The immune system and everything in it.
Engineered Th17 cell differentiation using a photo-activatable immune modulator - https://pubs.acs.org/doi/10.1021/jacs.0c07485 - Chang Lab at Cornell used a synthetic biology toolkit to selectively differentiate CD4+ T-cells into Th17 cells. The group developed a photo-activatable immune modulator that upon photochemical activation, agonizes the aryl hydrocarbon receptor (AhR) to begin the Th17 differentiation process. Th17 cells help T-cells target and kill extracellular pathogens and are co-located with mucose, and have a role in autoimmunity and allergies. The tool invented here will give others the ability to study Th17 cells in vivo and potentially connect this cell type with more diseases and pathways.
New Data for Vibostolimab (MK-7684), Merck’s Anti-TIGIT Therapy, as Monotherapy and in Combination With KEYTRUDA® (pembrolizumab) -https://www.merck.com/news/merck-presents-promising-new-data-for-three-investigational-medicines-from-diverse-and-expansive-oncology-pipeline-at-esmo-virtual-congress-2020/ - Merck released exciting data at ESMO on a new IO target: ILT4. The target is expressed on myeloid cells and is important for tumor evasion. Merck developed a human IgG4 monoclonal antibody targeting ILT4 (MK-4830). The MoA of MK-4830 is to inhibit ILT4 to reprogram tumor-associated macrophages leading to myelosuppression and enhancement of T-cell activity:
- Among 84 patients, 50 received MK-4830 monotherapy; 34 received MK-4830 + pembro (anti-PD-1).
- Preliminary efficacy data show 11 objective responses, with 2 complete responses and 9 partial responses
- What makes ILT4 pretty interesting, albeit let’s see where the clinical data plays out, is that it reduces immunosuppression imposed by tolerogenic myeloid cells in the tumor microenvironment. Some cancer indications, mainly those from the myeloid lineage, have issues with current medicines due to the lineage encoding for essential cells like red blood cells.
Biochemistry and structural biology
The granddaddy of them all.
Conformational states dynamically populated by a kinase determine its function - https://science.sciencemag.org/content/early/2020/09/30/science.abc2754.full - the Kalodimos Lab at St. Jude Children’s Research Hospital used nuclear magnetic resonance (NMR) spectroscopy to figure out how the Abl kinases, an important target in cancer and the target Gleevec engages, transitions from its active form to two distinct inactive forms. NMR is such a useful tool and the group uses it to find 2 inactive forms of Abl to create new scaffolds for new inhibitors to be developed. In general, drugging protein motion is a massive opportunity. Relay Therapeutics is likely just the beginning. Using cryo-EM, NMR, and other forms of spectroscopy will enable groups and companies to image proteins and cells are multiple scales - discovery entirely new classes of biology.
Neuroscience
Roughly 20 years behind but set up to transform the concept of human.
Impact of TREM2(R47H) variant on tau pathology–induced gliosis and neurodegeneration - https://www.sciencedirect.com/science/article/abs/pii/S0166223620301764?dgcid=author - the Holtzman Lab at WUSTL established the neuroprotective role of TREM2(R47H) in a mouse model of tauopathy. Triggering receptor expressed on myeloid cells 2 (TREM2) is a gene responsible for microglia activity and certain variants that decrease TREM activity like R47H have been found to increase the risk of Alzheimer’s by several multiples. Alector has a phase 1 study ongoing for an antibody to enhance TREM2 signalling in Alzheimer’s - https://investors.alector.com/news-releases/news-release-details/alector-announces-first-alzheimers-disease-patient-dosed-phase Like any medicine in neurodegeneration, developing biomarkers (i.e. PET tracer for tau and other toxic proteins) to identify the therapeutic window is incredibly important.
Negative feedback control of neuronal activity by microglia - https://www.nature.com/articles/s41586-020-2777-8- the Schaefer Lab at Mount Sinai establish the role of microglia in suppressing neuronal activity in an adenosine-dependent manner. The group identifies A1R, an adenosine receptor, as an interesting target to pursue for seizures and neurodegeneration. The key finding is that microglia protect the brain from abnormal activation. The next steps are to better understand A1R as a drug target, finding signals beyond ATP that activate microglia, and connecting this phenomena to things like metabolism and sleep.
Cell biology
Cell structure and function.
A Molecular Logic Gate Enables Single-Molecule Imaging and Tracking of Lipids in Intracellular Domains -https://pubs.acs.org/doi/10.1021/acschembio.0c00639 - the Rivera-Fuentes Lab at ETH Zurich invented a very useful photoactivated chemical probe to image cellular lipids in single-cells. Probes in general open up new fields in biology.
Regulation of Collective Metastasis by Nanolumenal Signaling - https://www.cell.com/cell/fulltext/S0092-8674(20)31087-4 - the Cheung Lab at Fred Hutch show, using a human breast cancer organoid model and a mouse model, that cancer cells generate the epigen growth factor that concentrate in compartments in between cells called nanolumina. These compartments are sealed by cell-cell junctions opening up a new target class for breast cancer and beyond. So cancer seems to be using nanolumina to signal metastatic cancer cells to grow. Epigen and localized signaling environments between cancer cells are new places to explore to treat metastatic cancer.
Genetics, genomics, and developmental biology
Heredity and variation.
A High-Resolution Map of Human Enhancer RNA Loci Characterizes Super-enhancer Activities in Cancer - http://cell.com/cancer-cell/fulltext/S1535-6108(20)30431-1 - the Liang Lab at MD Anderson use RNA-seq to map out superenahcers (group of multiple genetic enhancers) create a resource for others to use. Enhancer activity can be inferred from RNA products of enhancers from transcription. Arpeggio Bio is doing great work to productize this method -
https://arpeggiobiosciences.com/
Functional CRISPR dissection of gene networks controlling human regulatory T cell identity -https://www.nature.com/articles/s41590-020-0784-4 - the Marson Lab at UCSF published some incredible work to apply pooled CRISPR screens to transcription factors in Tregs. Tregs are important to regulate immune response; before the paper, FOXP3 was a well characterized transcription factor driving Treg development. The group screened for various knockout combinations under normal and inflammatory conditions (induced by cytokines). The group generated over 50K Treg transcriptomes under various conditions and sorted them for CTLA-4, IFNg, and FOXP3 to identify PRDM1, HIVEP2, FOXO1, and SATB1, IRF4 as other transcription factors important for Treg activity. This type of experiment will generate new Treg targets and importantly, provide a resource to design Treg therapies in oncology and autoimmunity (i.e. Sonoma Biotherapeutics). In general, single-cell, CRISPR screens are an efficient way to map out both intrinsic and extrinsic factors that drive a cell type. Successful drug companies can be formed off the basis of a pooled-CRISPR screen on Tregs, gamma delta cells, and beyond.