The Needle Issue #3

Welcome to the latest issue of the Needle, a newsletter from Haystack Science on preclinical biotech. If you are interested in science commercialization and how to take your early-stage discovery to market, this newsletter is for you. We aim to provide quick and insightful updates on preclinical research and the business around it every week. If you find the content helpful, please forward it to your friends and colleagues.

This week, we delve into the latest research and startup activity around biparatopic antibodies and look at startups at AACR. Elsewhere, it was a quiet/slow week for financings and deals. The buzz continues over ways to support innovative biomedical research and translational studies, given cuts in Washington.

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A growing stable of biopharma companies are developing biparatopic antibodies, which hit the same target via two non-overlapping epitopes. Compared with monospecific mAbs, such antibodies display enhanced binding through increased avidity, slower target dissociation, improved internalization, and greater specificity against drug target families where members share significant structural similarity. Now in the Journal of Clinical Investigation, a group at the Broad led by William Sellers describes biparatopic mAbs that inhibit fibroblast growth factor receptor 2 fusions, which are found in a variety of cancers, including intrahepatic cholangiocarcinomas (ICCs).

Sellers and his team showed that their mAbs inhibit signaling through FGFR2 fusions and inhibit ICC proliferation. They generated a panel of 15 biparatopic antibodies from 6 parental human antibodies and systematically tested them for their anti-proliferative activity on cells expressing FGFR2 fusions. Two showed greater potency than the parental antibodies, both in vitro and in vivo. Moreover, these biparatopic antibodies potentiated the action of FGFR2 inhibitors on cancer cells, and their inhibitory effect persisted, even against FGFR2 fusions with mutations that drive drug resistance. Mechanistically, the biparatopic antibodies promoted internalization and lysosomal degradation of FGFR2 fusions.

Sellers is also a scientific founder of Cambridge, Mass-based RedRidge Bio, which was funded in March via an undisclosed Series A venture round. Another recent startup, Attovia, took its first VHH biparatopic nanobody program against IL-31 into the clinic earlier this year and is collaborating with SciNeuro Pharmaceuticals on a neurology target.

The FGFR2 fusion work follows in the footsteps of studies by Regeneron demonstrating that biparatopic antibodies are effective inhibitors of oncogenic fusions of other receptor tyrosine kinases (RTKs). In that work, Regeneron researchers targeted fusions of another FGFR family member, FGFR3. In theory, the approach should be generalizable to any cancer arising from RTK fusions.

Biparatopic antibodies can work either in cis (binding the same target twice) or trans (binding two different molecules of the same target; e.g., to facilitate receptor clustering). Although they have been in clinical testing since 2011, it took until 2022 for the first biparatopic product to reach the market. Nanjing, China-based Legend Biotech (now J&J) got FDA approval for a T-cell therapy against refractory multiple myeloma featuring a chimeric antigen receptor (CAR) based on two single-domain antibodies targeting two different epitopes on B-cell maturation antigen (BCMA). Last November, FDA also gave the green light to Jazz Pharmaceuticals and Zymeworks’s zanidatamab, a biparatopic mAb that binds HER2 in trans and is indicated for patients with HER2-positive biliary tract cancer.

Similar to the antibody drug conjugate (ADC) space, a commercial stampede is currently underway in China to develop biparatopic mAbs against HER2, with at least 4 companies (Xuanzhu Biopharm, Alphamab Oncology, Chia Tai Tianqing Pharmaceutical and Beijing Mabworks) with products in clinical development. Given that big pharma has yet to make major announcements around biparatopic mAbs—notwithstanding AstraZeneca’s/Medimmune’s discontinued effort to develop MEDI4276, an anti HER2 ADC based on a biparatopic scaffold— the recent co-development partnership deal between Pierre Fabre Laboratorie and RedRidge Bio likely augurs more deal activity around this antibody modality in the near future.

Papers: Best of the rest

​Unraveling new target biology:

​ARID5A orchestrates cardiac aging and inflammation through MAVS mRNA stabilization | Nature Cardiovascular Research​

​Transcriptional regulation by phosphoglycerate dehydrogenase drives amyloid pathology: relevance to Alzheimer’s in population lacking mutations in APP, PSEN, or MAPT or of APOE4 risk allele | Cell​

​Metabolic signaling of ceramides via FPR2 receptor inhibits adipocyte thermogenesis | Science​

​Preclinical characterization of aberrantly cell surface expressed RNA-binding protein csNPM1 in AML models | Nature Biotechnology​

​Mycobiota medicine: naphthoquinone secondary metabolite from gut fungus inhibits ceramide synthase and ameliorates fatty liver in mouse models | Science​

​Long noncoding RNA BCYRN1 promotes cardioprotection by enhancing human and murine regulatory T cell dynamics | JCI

Therapeutic developments:

​A highly mobile adeno-associated virus targeting vascular smooth muscle cells for the treatment of pulmonary arterial hypertension models| Nature Biomedical Engineering​

​Facile generation of drug-like conformational antibodies specific for amyloid fibrils | Nature Chemical Biology​

​Design and structural basis of 1,4-dihydropyridine inhibitors selective for the calcium-activated potassium channel KCa3.1, with potential for hereditary xerocytosis | PNAS​

As synthetic lethal therapeutic approaches continue to ride high, two Nature papers highlight inhibitors of a new target combination in preclinical cancer models and of a combination of known targets in fibrosis:

​Simultaneous inhibition of PIKfyve-driven lipid metabolism and KRAS-MAPK leads to synthetic lethality in preclinical pancreatic cancer models | Nature​

​Simultaneous inhibition of SRC by saracatinib and TGF beta by pirfenidone suppresses cardiac fibrosis | Nature​

Last week saw two notable technology papers:

​A battery-free nanofluidic intracellular delivery patch for internal organs | Nature​

​Protein editing via inteins enables site-specific incorporation of noncanonical residues or chemical tags into recombinant proteins | Science​

This preclinical assay also caught the eye for those interested in rare disease:

​Bacteria expressing recombinant human enzymes containing variants of unknown significance in Mendelian diseases allow ​high-throughput assessment and drug screening​ | Nature Biomedical Engineering​

As did this review discussing cellular assays measuring ubiquitinase activity and the rneed to better understanding ubiquitination steps for PROTAC development efforts:

​Cellular parameters shaping pathways of targeted protein degradation​

Startup news

The big event from the past week was AACR in Chicago. ​Drug Hunter gave a summary of new drugs presented. An impressive array of startups from around the world presented treatments against difficult-to-treat cancers:

On the funding side, the news remains bleak:

​Global Data reports biopharma venture financing experienced 20.2% downturn during first quarter of 2025, with investors continuing to favor later-stage companies​

But VC funds are still being raised for seed financing:

​Deerfield closes $600 Million Healthcare Venture Fund aimed at seed investments in therapeutics and AI technologies​

Two startups were profiled:

​France’s CEA Institute highlights spinout developing V4C-232 peptide derived from toxin extracted from mamba venom to treat refractory ascites in liver cirrhosis and other cardio-renal diseases.​

​Aera Therapeutics pivots to validate lipid nanoparticle vehicles while continuing to iron out kinks in its platform protein nanoparticle delivery system

Meanwhile, industry and government leaders continue to react to the US administration's changes to biomedical research funding:

​Roche announces 5-year $50 billion investment in USA and establishment of R&D center in Massachusetts focused on AI research and cardiovascular, renal and metabolism​

​Digitalis Commons highlights changes to preclinical research funding from philanthropies, family offices, regional governments, private investors, disease foundations, and crowd-funding.

​European Commission announces $565 million package to retain European researchers and attract US scientists​

​Biotech leaders at Stanford’s Drug Discovery Symposium share their concerns about Trump policies​

And if you are a early-stage founder seeking non-dilutive funding, check this out: Illionois Bioindustry Innovation Organization (iBio) publishes guide to non-dilutive funding​

Preclinical funding

Preclinical deals

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Stay in touch

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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).

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Until next week,

Juan Carlos and Andy