The Needle Issue #20
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Welcome 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. In this issue, we look at one of biotech’s hottest areas—multi-specific antibodies. Although the hype has somewhat dissipated since Akeso’s September announcement of disappointing overall survival data from the HARMONi-A study of its bi-specific (PD-1 x VEGF) ivonescimab in lung cancer patients, multi-specific antibodies featured in the top three licensing deals and in the second-largest merger of the year. Financings of preclinical startups continued to tick over, with Yale’s Craig Crews’ latest induced-proximity degrader startup, Quarry Thera, catching the eye. This on the back of J&J’s announcement of a $3 billion buyout of an earlier Crews venture: regulated induced-proximity targeting chimera (RIPTAC) developer Halda Therapeutics. Preclinical deals continued to tick over, with several deals from GSK. As usual, anything we missed in the biotech startup world, let us know (info@haystacksci.com).
Haystack chat By our count, there are now 15 bi-specific antibodies approved by the US Food and Drug Administration (the last peer-reviewed count from 2024 we found chalked up 13). This year has been a bumper year for bi-specifics — antibodies that recognize two molecular targets. Several of 2025’s largest deals have involved assets in this class, including Genmab’s $8 billion acquisition of Merus in September and Takeda’s $11.4 billion splurge on an anti-Claudin18.2 bi-specific antibody and antibody-drug conjugate (ADC) from Innovent Biologics. Not only is this trend likely to continue, but we predict that it will expand to encompass tri- and multi-specific antibodies, the development of which is an area of intense research activity. Just a couple of weeks ago, South Korea’s Celltrion clinched a $155 million (biobucks) deal for TriOar’s tri-specific ADCs for cold tumors. And at the SITC meeting last month (which we covered in issue 19) tri-specifics were highlighted by no less than five companies: Nextpoint (B7-H7 x CD3 x TMIGD2), CrossBow (cathepsin G peptide x CD3 x CD28), TJ Biopharma (CDCP1 x CD3 x 4-1BB), Biocytogen (DLL3 x CD3 x 4-1BB) and Radiant Therapeutics (potentially tri-specific/trivalent). Building an antibody that recognizes three or more targets at the same time is not trivial, though. There are multiple technical, clinical and regulatory hurdles that developers need to overcome before the antibody reaches patients. Why, then, go through the trouble of creating a multi-specific antibody when a bi-specific may show clinical benefit? As it turns out, there are several reasons why a multi-specific antibody may be worth the effort. First, as tumors often escape by downregulating or mutating a single target epitope, a multi-specific antibody may reduce the likelihood of escape by simultaneously targeting multiple tumor antigens. Second, multi-specifics could increase safety and reduce toxicity of a therapy. For example, a multi-specific antibody can be designed to require co-expression of two or more antigens on the same cell to bind effectively. Healthy cells expressing only one antigen would be spared, thereby reducing off-tumor toxicity. Similarly, targeting multiple mechanisms with a single antibody may reduce the need to use several separate drugs, simplifying dosing and reducing risks for patients. Third, and perhaps most important, a multi-specific antibody can simultaneously block several disease pathways, yielding synergistic effects that a bi-specific might not achieve. In solid tumors, for example, tumor heterogeneity, limited immune-cell infiltration and an immunosuppressive microenvironment often result in therapeutic failure. Multi-specific antibodies could combine tumor targeting, immune-cell recruitment and checkpoint modulation in a single molecule. Perhaps the best example of this comes from the field of T-cell engagers (TCEs). A tri-specific antibody can incorporate not only tumor-cell binding and CD3 engagement, but also a co-stimulatory domain, such as CD28. This can boost T-cell activation, persistence and potency more than a bi-specific that only binds to CD3. In this regard, a recent paper in PNAS is an excellent example of the power of the approach. A research team from EvolveImmune Therapeutics reports on the development of EVOLVE, a next-generation TCE that integrates CD3 binding with CD2-mediated co-stimulation to enhance T-cell activation, durability and tumor-killing capacity, while avoiding target-independent toxicity. Conventional CD3-bi-specific TCEs activate T cells through a stimulation signal but often fail to provide the complementary co-stimulation necessary for sustained effector function. This can result in T-cell dysfunction, reduced persistence and limited clinical durability. To address this, Jeremy Myers and his colleagues systematically compared multiple costimulatory pathways and identified CD2 as a superior target owing to its broad expression on naïve, activated and exhausted CD8⁺ T cells, and its sustained expression within tumor-infiltrating lymphocytes. The team engineered tri-specific antibodies that fuse a CD58 extracellular domain (the natural CD2 ligand — Lymphocyte Function-Associated Antigen 3;LFA-3) to affinity-tuned CD3 binders within an IgG-like format. They showed that integrated CD2 co-stimulation substantially improves T-cell viability, proliferation, cytokine production and cytotoxicity across tumor types. When optimizing the molecule, they found that CD3 affinity must be attenuated: high-affinity CD3 domains cause target-independent T-cell activation and cytokine release (superagonism), whereas intermediate-affinity variants retain potent tumor-directed killing with reduced off-target activation. The EVOLVE tri-specifics outperformed matched bi-specifics targeting HER2, ULBP2, CD20 and B7-H4, with increases up to >50-fold in potency, depending on the target. The optimized tri-specifics also showed superior tumor control in vivo, achieving durable tumor regression in humanized mouse models even after cessation of the treatment. Even though tri- and multi-specific antibodies could offer clear advantages over bi-specifics, they are not without problems. From the technical standpoint, multi-specifics combine multiple binding specificities and often non-natural architectures. This feature increases complexity at every step from discovery to manufacturing. The assembly of IgG-like multi-specifics can result in heavy/light and heavy/heavy chain mispairing leading to heterogeneous products. Although antibody engineers have come up with strategies to address this issue, each solution adds constraints to developability. Multi-specific antibodies can also have lower expression, cause more host-cell stress and require more advanced cell-line engineering or multi-vector expression systems. Moreover, downstream purification often needs additional steps to separate mis-paired species. Similarly, multi-specific antibodies are often less stable, more aggregation-prone, and more sensitive to formulation conditions, impacting shelf life and immunogenicity risk. It is also important to show identity, purity and functional activity for each specificity and for the multi-specific activity (that is, simultaneous binding, cell-bridging). So, establishing robust potency assays is often the greatest challenge. What is a good model system to design a development candidate going after several targets at the same time? With each additional binder, complexity in discovery and development increases. From the clinical standpoint, although multi-specifics can potentially be safer than bi-specific antibodies, as we mentioned above, other toxicological risks exist. TCEs have been known to trigger cytokine-release syndrome, neurotoxicity, or unexpected tissue toxicity if targets are expressed on normal tissues. First-in-human dosing strategies are therefore critical. Moreover, multi-specifics may have non-linear pharmacokinetics (target-mediated clearance for each target), and dual-target engagement can alter distribution and half-life; selecting a safe, effective dose requires integrated PK/PD modeling and biomarker strategy. And the headaches don’t stop there. Efficacy of a multi-specific may depend on co-expression of two or more targets. Stratifying patients may therefore complicate trial enrollment and endpoint definition, not to mention that it may be necessary to develop companion diagnostics (already expensive and complex for conventional monoclonal antibodies). And related to this point, when multiple targets are engaged, it can be hard to know which specificity caused an adverse event, complicating risk–benefit evaluation and mitigation. Finally, from the regulatory perspective, although expectations are still evolving, agencies expect a pharmacological package that reflects multi-specific mechanisms, particularly with regards to toxicology. Regulators routinely require robust control strategies to ensure product consistency. Again, this is going to be more complicated for multi-specifics because small changes in manufacturing can alter pairing or potency. Multi-specific antibodies are gaining momentum. They represent a potentially powerful technology, but many questions still surround their development. Success may depend on striking the right balance between choosing the appropriate therapeutic indication, identifying the simplest effective format, heavy upfront developability and analytical work, and early interactions with regulators to align on pre-clinical packages. Translational papers: Best of the rest Target biology Elucidating pathway-selective biased CCKBR agonism for Alzheimer’s disease treatment | Cell NSD2 targeting reverses plasticity and drug resistance in prostate cancer | Nature Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration | Science Proof-of-concept studies Cancer immunotherapy Platforms, delivery, editing Prime editing-installed suppressor tRNAs for disease-agnostic genome editing | Nature Startup news Atlas Venture’s Year in Review video is out. As usual, it’s chockfull of detailed information about current state of pharma and biotech. To whet your appetite, these graphs show that biopharma’s share of venture funding in the US has markedly declined since the COVID-era peak, mirroring a reduction in the number of biotech investors. Over the other side of the pond, two high-profile European venture-capital firms announced large funds for early-stage companies: Medicxi Announces €500 Million Fund V Elsewhere, mega-fund Flagship Pioneering—which distributes close to ~500 million every year and now has 40+ active biotech ventures within its ecosystem (akin to a small country!)—announced strategic partnerships in Saudi Arabia and the UK: It also announced a second fund-wide big pharma deal with GSK (following 2023’s deal with Pfizer): Elsewhere, large-cap companies are investing in Philadelphia and ‘Cellicon valley’: Lilly plans fourth US Gateway Labs in Philadelphia to spur biotech startups And Abbvie is reaching across the border: While government funding is dwindling, ARPA-H announced a program to invest in databases detailing mental health readouts for neuromodulatory drugs: Another funder, The Wellcome Trust, has announced a partnership with the UK’s Academy of Medical Sciences to support UK translational researchers: Meanwhile, National Taiwan University has followed the trend of universities starting their own funds: National Taiwan University launches 30 million fund to kickstart local innovation Hundreds of biotech leaders sign letter to FDA emphasizing importance of decision-making consistency, transparency and speed to support industry innovation: 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 week, Juan Carlos and Andy |