The Needle Issue #12
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Welcome back to The Needle, a newsletter from Haystack Science to help you navigate the latest translational research, with a roundup of the latest news on preclinical biotech startups from around the world. After a brief summer hiatus, we are delighted to be back. This week, in the context of all the chatter about in-licensing Chinese assets, we highlight a novel target originating from a Hangzhou City biotech. P-selectin glycoprotein ligand-1 (PSGL-1) is a new member of the growing target class of phagocytic checkpoints, which includes CD47/SIRPa, disialoganglioside (GD2), leukocyte immunoglobulin-like receptor subfamily B1 (LILRB1) and CD24 (Siglec10) among the examples with drug programs farthest in clinical development. On the investment front, despite the funding doldrums, venture funds across the world purporting to seek “early-stage” investments keep on being raised. And the UK government also announced a big biotech push with its ‘Life Sciences Sector Plan’. It may be summer, but the financings (including a $216 megaround series A) and deals keep ticking over. Any that we missed, let us know (info@haystacksci.com).
Haystack chat The Summer BIO report “The State of Emerging Biotech Companies: Investment, Deal, and Pipeline Trends” highlights how much China-based programs have contributed to the drug pipeline over the past 10 years. A couple of weeks ago, Bloomberg also summarized deal data showing how the share of global licensing by Chinese biotech companies has jumped over the past two years. Judging by a report listing 16 ‘high-value’ currently unlicensed assets from China being hawked by longtime Phalanx Investment Partners analyst David Maris, there is more licensing to come. In this context, we read with interest a recent Science Immunology paper describing a monoclonal antibody (mAb) program targeting a novel phagocytic checkpoint under development at yet another Chinese biotech: MedimScience, founded in Hangzhou City in 2021. MedimScience is one of a growing cadre of companies, including LTZ Therapeutics, Dren Bio, Chengdu Kanghong, Antengene and ImmuneOnco, looking to develop novel myeloid cell engagers/phagocytic checkpoint inhibitors. Phagocytic checkpoint inhibitors are drugs that circumvent the molecular cloaks that tumors throw around themselves to avoid uptake and destruction by myeloid cells, such as macrophages, monocytes, and neutrophils. The strategy first came to the fore through pioneering work on the ‘don’t eat me’ signal CD47, work carried out by Ravi Majeti and Irv Weissman at Stanford. Results from their preclinical studies spurred the launch of startup Forty Seven (subsequently acquired in 2020 by Gilead) and the first-in-class anti-CD47 IgG4 magrolimabprogram.Phase 1b trial results of magrolimab combined with azacitidine in acute myeloid leukemia (AML) patients were so impressive that, by 2022, more than 20 different companies had anti-CD47 programs in clinical development. This blew up spectacularly when early trials failed to be reproduced in larger efficacy trials of combinations — failure that was largely attributed to intolerability/anemia issues related to the target, slow action/early disease progression, and a failure to account for patient heterogeneity with regard to P53 mutation status. But the strategy is compelling and the hunt for new phagocytic checkpoints has continued with new antibody formats seeking to avoid these pitfalls. Now, Cheng Zhong and his colleagues at MedimScience report the identification of a new evasion actor — PSGL-1 — that suppresses macrophage-mediated phagocytosis in a variety of hematological malignancies. PSGL-1, which was previously known largely for its role in cell adhesion, is highly expressed in various hematologic cancers, including AML, T-acute lymphoblastic leukemia (T-ALL) and multiple myeloma (MM). Moreover, high PSGL-1 expression has been found to correlate with poor patient survival in AML, T-ALL and MM. Using several mouse models, the researchers found that tumors lacking PSGL-1 show slower progression, increased macrophage infiltration, and higher rates of phagocytosis by macrophages, effects that were independent of T cells or dendritic cells. Mechanistically, the team found that PSGL-1 disrupts the interaction between the cell-adhesion molecule ICAM-1 on tumor cells and the integrin LFA-1 (CD11a/CD18) on macrophages. And when they tested Novartis’ lifitegrast, an inhibitor of ICAM-1/LFA-1 binding, they found this largely abrogates the phagocytosis of PSGL-1 knockout tumor cells, confirming PSGL1’s role in impairing prophagocytic signaling and cytoskeletal reorganization required for effective tumor-cell engulfment. The authors went on to develop a humanized mAb against PSGL-1 and show its ability to induce phagocytosis of human tumor cells in vitro and to reduce tumor burden in mouse models of AML, T-ALL, and MM. The antibody showed a good safety profile in non-human primates with no significant toxicity at high doses. Additionally, PSGL-1 blockade synergized with chemotherapy (doxorubicin) and antibody-based therapies (anti-CD47 and anti-CD38), further underscoring the translational potential of this strategy, particularly in treatment-resistant settings. Papers: Best of the rest Target biology A mast cell receptor mediates post-stroke brain inflammation via a dural-brain axis | Cell The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity | JCI Proof-of-concept studies NSD2 inhibitors rewire chromatin to treat lung and pancreatic cancers in mice| Nature Immunotherapy Design of soluble Notch agonists that drive T cell development and boost immunity in mice | Cell LARP4-mediated hypertranslation drives T cell dysfunction in tumors | Nature Immunol De novo design and structure of a peptide–centric TCR mimic binding module | Science De novo-designed pMHC binders facilitate T cell–mediated cytotoxicity toward cancer cells | Science Design of high-specificity binders for peptide–MHC-I complexes | Science Cancer immunology data engine reveals secreted AOAH as a potential immunotherapy | Cell ACLY inhibition promotes tumour immunity and suppresses liver cancer | Nature A CD4+ T lymphocyte–specific TCR/GSDMD/IL-2 axis facilitates antitumor immunity | JCI Delivery platforms Genome editing Design of highly functional genome editors by modelling CRISPR–Cas sequences | Nature AI-generated MLH1 small binder improves prime editing efficiency | Cell In vivo prime editing rescues alternating hemiplegia of childhood in mice | Cell Startup news The UK launched its Life Sciences Sector Plan: Although university spinout funding is in the doldrums, venture funds are still raising dollars for “early-stage” biotech: Swiss-based Omega Funds rounds up $647 million for eighth fund for biotech startups Biogen builds a ventures team internally to find, finance and build external assets Since the 2021 peak during the COVID-19 pandemic, venture capital raises in the biopharma industry have declined. Money is creeping back to the sector via bigger raises at fewer funds: The silver lining is especially evident in Asia/Oceania: National University of Singapore launches $78 million spinout fund for startups Singapore-based Origgin launches venture fund II with $23 million for Asian university spinouts Australian-based Brandon Capital raises $287 million for sixth fund for biotech startups Recent weeks have seen several accelerator campaigns to attract startups: Freshly funded UK accelerator Slingshot invites applications from UK life science startups Canadian adMare Academy releases report on Canadian biotech, with applications closing on Sept 5 for its Executive Institute for life science entrepreneurs interested in honing company building skills/network Last, some news on grant awards for translational research around the world: Preclinical financings Preclinical deals Stay in touch We hope you enjoyed this issue of The Needle and hit the button below to receive forthcoming issues into your inbox
If you’re interested in commercializing your science, get in touch. We can help you figure out the next steps for your startup’s translational research program and connect you with the right investor. Follow us on X, BlueSky and LinkedIn. Please send feedback; we’d love to hear from you (info@haystacksci.com). Until next time, Juan Carlos and Andy |