Sebastian Palluk

We recently sat down with Dr. George Wang, Vice President of Discovery and Preclinical Services at WuXi Biologics to discuss the importance of looking at developability of an antibody early in the drug discovery process. In the podcast, The Importance of Evaluating Developability in the Antibody Discovery Stage, Dr. Wang defines developability and its significance in achieving scalable production during CMC development, which is essential for large-scale manufacturing before clinical trials. He emphasizes the importance of identifying and addressing developability concerns early in the discovery stage to mitigate risks and ensure cost-effective development. Dr. Wang provides examples where developability studies have helped prevent unforeseen costs and timeline disruptions during biologics discovery and preclinical development phases. He underscores that assessing developability can reveal issues with product aggregation, stability, solubility, or manufacturing efficiencies. https://lnkd.in/g7qY9kXs

2

From the preprint: In this study, we introduce HiBiT-RR and nLucK0, variants devoid of lysine residues, to mitigate such artifacts. Our findings demonstrate that HiBiT-RR maintains similar sensitivity and binding affinity with the original HiBiT. Moreover, the comparison between nLucWT and nLucK0 constructs reveals variations in degradation patterns induced by certain PROTAC molecules, emphasizing the importance of choosing appropriate tagging systems to ensure the reliability of experimental outcomes in studying protein degradation processes.

12

1 Comment

The FY2024 House National Defense Authorization Act (NDAA) is a bill of significant importance, and its implications for WuXi and the US biotech landscape are worth noting. According to CEO Rick Connell, "We're reading the context of the bill, and it's all about human genome sequencing data. We genuinely did not understand why we were inserted into the bill." It appears that Congress knows more about WuXi than their CEO! Let's delve into this together and read this article to learn more about the bill's impact on WuXi and the implications for the US biotechnology landscape. #FY2024 #NationalDefenseAuthorizationAct #WuXi #biotech #genomesequencing

2

Over the weekend I was thinking (as one does 🤪) about Illumina moats. A clear sign that they're less effective than they've been historically is the traction that Element Biosciences has in the benchtop space, and MGI's success in overcoming Illumina's long held IP moat. I've heard that concern aboutthis problem drove Illumina's focus on vertically integrating via the GRAIL acquisition; I think it's fair to say that didn't work both because of regulators and it wasn't a real thing. So what's a monopoly to do? Obviously try and catch next the week wave - in my opinion that's proteomics sequencing - but that's going to take a lot of time and investment and technology risk. What can be done right now to shore up the moat as it's at immediate risk? One idea would be to license its core SBS technology to other life science companies. Some of the pros and cons: PROS: - Lets OtherCo's do the vertical integration. A great example of this is what Thermo Fisher Scientific has done with Genexus - built a clinical grade sample to answer system around Ion Torrent technology. Illumina has nothing like this because it doesn't have the extraordinary breadth of IVD experience and technologies that Thermo brought to the table. Why not license SBS to companies with these capabilities such as Danaher Corporation, QIAGEN and Roche? - Flexible high margin business model. Sure at one end of the licensing spectrum is royalties with 100% margin but low revenue, but there also the option of selling consumables. The seed for that model can be seen in the new MiSeq: all the complexity/IP is in the consumable (CMOS, fluidics, etc), very little in the instrument. Perfect for partnerships - you guys build the razors and we'll build the razorblades. - Licensing creates amazing moats as it turns potential large-company competitors into customers. It's a win-win for those customers: they get access to a constantly improving low risk NGS technology while being able to focus on their true value added, which is in non-NGS things. - I'm guessing this wouldn't be a problem for regulators - they would see it as a good thing as Illumina is sharing it's IP with others which feels anti-monopolist. CONS: - Potential for cannibalizing Illumina sales with licensee sales. This requires careful choice of licensees and limiting their field of use e.g. licensing SBS to Qiagen to only build a clinical sample to answer. And maybe picking winners here would be an anti-trust issue? Dunno. - Leakage of IP to licensees - Other? Struggling a little for a business analogy there. Kind of like Arm: a true platform with a great moat and scalable business model; customers for sure build vertically integrated solutions around their IP. Any other pro/con suggestions or business analogies?

56

8 Comments

A new study from Westlake University introduces #Pinal, a groundbreaking approach to de novo protein design using natural language guidance. 🎯 This new tool generates protein structures from language inputs and then designs sequences based on both structure and instructions. It outperforms existing models in creating diverse, functional proteins from scratch. This two-stage method promises to expand the frontiers of protein engineering. Quick Read: https://lnkd.in/g4CMkDzH #bioinformatics #proteindesign #proteinlanguagemodels #LLM #AI #syntheticbiology #proteinengineering #drugdiscovery #sciencenews

47

1 Comment

I think we're seeing a whole new Illumina strategy for defending the mid-market from Element Biosciences competition. I for one was thinking too narrowly to see this - figured it was all about Aviti vs NextSeq. But I think we're starting to see a clever three-pronged Illumina strategy: (1) Times are hard, why buy a mid instrument for $400K when you can just skip that and send your samples out to someone with an X? (2) High throughput is where it's at, here's a cheap NovaSeq X, why not stretch a little for that and be able to hang with the cool kids? (3) Have you seen our new MiSeq i100? Here take this Lego one. It's just $100K, you can most of your stuff with that, and just send out for the big stuff. Sure, kills NextSeq sales too, but that's easy pain for Illumina to bear, but existential for Element. Here's Illumina CFO Ankur Dhingra spelling it out for Wolfe's Doug Schenkel: "...customers, because of the macro [economic/grant] issues, have been transitioning their sample volume to high throughput. And a lot of our mid throughput customers who are constrained by that macro environment are resorting to sending their samples to either core labs or other sequencing providers." "...the constrained environment is making people take decisions on what are they going to invest in their lab or until money frees up, they're going to take advantage of the lower high throughput [X-based sequencing as a service] pricing that is available externally." "I do think there are additional two factors that are coming our way from an Illumina perspective. We have said we will be launching a slightly lower throughput version of NovaSeq X with a single flow cell. And that is at a price point which is well below 1 million. So, there is a potential that some of our mid throughput customers may see some value there. And also, the higher end of the new MiSeq i100 that we have launched has capabilities that can seep into some of the mid throughput kind of requirements as well. So, it's [Element?😳] going to get squeezed from a little bit from both the directions as well."

159

22 Comments

Great thing to know if you are one of them using #cell based #HT platforms that facilitates using Rapid #PROTAC discovery, nanomole scale array synthesis and direct screening of reaction mixtures.

2

Trying to get my head around the strategy/game theory of this Illumina GRAIL spinoff (not an investment banker 🤣). It's very different from a normal deal because of the EU mandate: MUST divest & MUST add $1B if a spinoff. Seems to have 3 phases (M&A people feel free to weigh in with corrections/color): Phase 1 (completed Feb 24) Illumina hires 2 serious investment banks (JPM and Centerview) to run an M&A auction for Grail. Banks contact all likely (and unlikely) parties, interested parties go under NDA, do due diligence, maybe make an offer. I heard Illumina's ask was something like $2B so maybe potential buyers are thinking $1B. But no one makes an offer - we know this because any reasonable offer would be better for Illumina than moving to phase 2: Phase 2 (completed May 24) Lacking an offer, Illumina announced its plan to spin-off Grail to Illumina shareholders after adding the EU-mandated $1B to the deal. Really a last resort option because of the $1B which comes from Illumina cash unless the bankers can stitch together a PIPE which feels unlikely given the negative signal sent by the failure of Phase 1. Also the uncertainty of where GRAL stock will trade, could be (even more 🤪) embarrassing. Phase 3 (underway now) Here I'm really spitballing because the situation is so unusual. Let's say that some of the potential acquirers in Phase 1 were kind of interested but not prepared to pay much. Now they know that Illumina is down to its worst possible option, putting $1B into the spinoff. Maybe go back to Illumina and offer to take Grail off its hands for $0 if Illumina just puts in say $500M? That way Illumina saves $500M and eliminates the risk of floating GRAL. But if this was interesting to the acquirer it makes more sense to let the spinoff happen and then take GRAL private with $1B in the bank. Ah, that's why Illumina put the change-of-control prorated clawback in the spinoff docs 👏 Fascinating and unusual situation 🍿🍿🍿

76

34 Comments

Scientists at Stanford University introduced #Protpardelle, a novel all-atom diffusion model for #proteindesign. This innovative model represents all sidechain states simultaneously, enabling the co-design of protein structure and sequence. Could this lead to more efficient drug discovery? Quick Read: https://lnkd.in/gJxA8r9Q #bioinformatics #proteindesign #AI #GenerativeAI #drugdiscovery #sciencenews

55

Hey LinkedIn Fam - Help out Narwhal Bio! As part of the BioTools Innovator competition, Narwhal has put out a 1 min video about what we're building. The video will be part of a number of factors the BTI team of of advisors will use to rank the companies. Please go to Youtube and "Like" the video as exposure counts! https://lnkd.in/gc6zFqGf Please also "Like" this post below to keep it at the top of people's feeds! Thanks everyone!

53

1 Comment

Our GenAI for sequence and structure generation of paratopes in action

13

A couple of weeks ago Illumina filed a motion to dismiss the major "Kangas" suit against Illumina executives and directors. There's a lot in there - it's about 40 pages of defensive arguments - but the argument I find most cynical is that statements on the lives to be saved by GRAIL by Illumina executives and board members were simply "puffery". In a legal context "puffery" refers to exaggerated statements made by sellers to promote their products or services. For example, a restaurant advertising its dish as “the best pizza in the world” is engaging in puffery. Courts generally consider puffery be viewed as opinions that no reasonable person would rely upon as factual assertions. Here are examples of statements by Illumina executives that Illumina now claims were simple puffery: "statements that the merger would “save lives”" "statements that the merger would “dramatically accelerate getting this test into the hands of people whose lives it could save"" "statements that the merger would enable Illumina to bring Galleri to “patients across the world faster and consequently save lives” So, Illumina itself is now admitting that everything they said about GRAIL saving lies was just bullshit. That's their defense. No shame. 🤯🤯🤯

127

28 Comments

Lead optimization is recognized as a highly complex and costly phase in antibody discovery. To improve lead quality, many labs are establishing early developability screenings. Back in 2017, the well-known PNAS paper by Jain et al. generated a lot of interest. Their team characterized 137 clinical stage mAbs using a dozen different biophysical methods, aiming to improve lead selection. However, no clear consensus emerged within the scientific community regarding which assays are most critical, prompting companies to develop their own individual strategies. When we speak with our users today, we observe broad agreement that hydrophobic interaction chromatography (HIC) and self-association assays (such as AC-SINS) are generating valuable data. There is also increasing recognition of Heparin binding as a potential predictor of PK. But when it comes to polyspecificity, things get murkier. Many existing assays rely on complex preparations from baculovirus or membrane proteins, which suffer from batch-to-batch variability, or ELISA assays, which are inconsistent due to the multiple washing steps involved. While many in the industry recognize these limitations, they often find themselves without viable alternatives, as none of these assays are available as reliable commercial products. We at PAIA aim to fill that gap by offering a growing range of developability assay kits. They feature no-wash protocols and use simple, chemically defined reagents, providing a more reliable way to generate critical biophysical data. #developability #antibodydiscovery #leadoptimization #screening

21

1 Comment

Excited to share this new work from our team at Schrödinger! This work marks a significant milestone in the field of formulations, being the first to apply screening at such a large scale with over 30,000 formulations and utilizing new machine learning models (set2set). The dataset and models established will greatly benefit the materials community, serving as a benchmark for new models and guiding the design of formulations for various applications. This outstanding work by Alex Chew and the team is an important step towards integrating physics-based modeling with machine learning in formulations. I am excited to see its application across different domains, such as drug formulations, consumer packaged goods, and energy storage. #MachineLearning #Formulations #MaterialsScience `#Research #PhysicsBasedModeling

33

🎉 10,000 downloads! 🎉 When I launched the Smart Biotech Scientist Podcast last November, I never imagined we'd hit this milestone so quickly. From lab bench to large-scale production, we simplify bioprocessing one episode at a time. To all the brilliant minds tuning in during their commutes, late nights at the lab, or coffee breaks - thank you! Here's to making biologics development less of a headache and more of an adventure. What topic should we tackle next? Drop your ideas below! 👇 #cellculture #processdevelopment #bioprocessing #biotech #cellandgenetherapy #podcast

48

14 Comments

Here's fun thought. We all know Illumina's umm "high" antitrust profile makes it a challenge to acquire anything. But an interesting (interesting to me anyway 🤪) upside of that is the Hart-Scott-Rodino (HSR) Act (passed to give the FTC enough time to make an antitrust judgment prior to deal closing). HSR sets a deal value threshold, that is annually adjusted, under which a deal pretty much (not an antitrust lawyer 🤣) doesn't get looked at by the FTC. This year the threshold is $120M - so we know that Fluent BioSciences Inc. sold to Illumina for less than that otherwise there would be all sort of fine print in the press release about 30 days to close yada yada. But here's the thing. Let's assume that Illumina wants to go around and buy a bunch of early stage LS companies of which Fluent is just the first. Negotiation goes like this: Illumina: Hi there! NewCo: OMG you're illumina you have tons and tons of $$$ even after GRAIL and we're the bestest spacial genomics/proteomics/bioinformatics company in the world so you can buy us but we we are worth $1B. Illumina: OMG you're right these are great slides we'd love to pay you $1B but the HSR limit this year is $120M so that's all we can pay so sorry, regulators gonna regulate 🤷‍♂️ NewCo: OK $119M and no earn-outs OK? Illumina: 🥳 Sometimes our greatest weakness is our greatest strength 🧘🏻

74

7 Comments

Wow, I think we're really witnessing the Apple-ification of Illumina 👏👏👏 Jacob has really been focusing his messaging on offering customers a full NGS vertical and this new MiSeq seems to embody that vision very well. There's virtually no mention of $/Gb in the announcement (folks are scrambling to try and decode that) - tag line is "Fastest, simplest. For every lab." Steve Jobs famously envisioned the Macintosh as an "appliance" - a computer for everyone vs its predecessor Apple 2 which was a computer for hobbyists (we're now called geeks). This MiSeq evolution follows that Apple evolution pretty well. Obviously not a consumer product, but MiSeq has been radically improved in terms of ease of use that may create some elasticity in this stale market: - Room temperature simple-to-load cartridge: 3 steps/20 minutes. - Much faster run times (4X faster than old MiSeq) - Seamless integration of DRAGEN (local) and BaseSpace (cloud) Technically there's a radical technology change underling the new instrument: its hardware is based not on the old MiSeq design, but on the flowcell-on-CMOS design of the iSeq. That means that (I think, not an engineer 🤣 oh wait am an engineer 🤣) ALL the optics and ALL the fluidics are in the consumable. This flips the economics of the old MiSeq on it's head as the instrument becomes super cheap - it's just a box with a computer and a display - and the consumable gets more complex as it contains the CMOS imager chip that gets thrown out each run. BUT the utilization of MiSeq has never been that high - sits in the corner a lot - so maybe this is fine 🤔 Two misses in my opinion: - No sign yet of any simplification of the product line. Do we need MiniSeq and the iSeq 100? Can't the new instrument replace both of these plus the old Miseq?! Maybe one low cost/high margin instrument platform with a range of consumables of varying capacity? - WTF with the nightmare new name that I've avoided saying up until this point 🤯🤯🤯 MiSeq i100 🤯🤯🤯 You took too old names MiSeq and iSeq 100 and jammed them together and kept the iSeq 100 in the product line?! Why not call this something new and simple like, I dunno, Macintosh 🤣, and position it as replacing the old MiSeq, MiniSeq, and iSeq 100. This would distinguish the new instrument from the MiSeq which will have to be around forever for the DX version. Grrrr. Anyway, if a dumb name is the worst thing here, that's a big win for Illumina, congrats to all involved. Nice first major product launch under Jacob that delivers on differentiating beyond price. Could have made a bigger splash compltely reimagining the product line - but maybe he's more Tim Cook than Steve Jobs - ain't nothing wrong with that! 👏👏👏

376

44 Comments

Lifting this really interesting comment from Shana McDevitt (Cal Seq Lab Director) into its own post. Lots to learn here about the Element Biosciences/Illumina competitive dynamic. Points that jump out to me: - Reminder that accessing low $/gb of an X doesn't require owning an X, you can send out to a service lab with an X. This weakens AVITI's low $/gb competitive advantage over Next Seq. - Users still want/need access to NextSeq, so AVITI is an add, not a swap and if you only own a single NextSeq, it's a 2X investment. - Trinity features may drive some new business, but TBD of course. - Overall reminder how tough an AVITI sale is against an incumbent NextSeq, making Element's new 300 sold number all the more impressive 👏 (Thanks Shana! Would love to hear more comments from lab directors 🙏) Comment: "I outsource for the X, there is a point where it just makes sense to pump lanes onto other ppls gigantic machines and keep their rates down. No service contracts for me and I don’t have to drop any CAPEX. UCB sized out at the 6000, we’re basic research we don’t pump out single cell or clinical sequencing. Ultimately I get my data back faster and cheaper." "AVITI is a midsize sequencer and I already have a NextSeq2k. The AVITI isn’t driving new business (trinity might) or creating a new market for me it’s just competing with what I have. So to get an AVITI I would move my NextSeq2k business and turn that off. Users are scared to transition so instead I would have 2 machines & service contracts." "If you can’t buy out right you can do a reagent loan deal generally with newer riskier vendors. No money down but you pay a markup on reagents. But, then AVITI is more expensive than Illumina and it’s “scary”. And Element really really worked with me, I may have had the best deal ever but any risk is just too much for a full cost recovery academic core in a deficit." "Long story short: I’m competing with myself and paying to do it. That’s bad business. I’d rather negotiate to turn on a machine I already own. I’ll do that business instead."

67

44 Comments

Spot-on analysis of Illumina's financial history from startup, with a focus on Jay Flatley's legendary ability to keep a cap on expenses before GRAIL destroyed that discipline. Well worth a read if you're involved in a company that’s finding its way through today's brutal funding environment (or current ILMN management 😥): https://lnkd.in/gAZ6VHbj "Adversity breeds resilience. Just ask Illumina. No, not that Illumina. The OG Illumina led by Jay Flatley." "Recent [Illumina disastrous] history distracts from the blueprint Flatley and the primordial [🤣] team laid down for everyone who followed. Almost no one has paid attention, but biotech's current funding dry spell suggests aspiring entrepreneurs should be taking notes." "Operating efficiency is a lost art in company formation. Despite having a blueprint for over two decades, no other biotech company serving the R&D inputs sector has come close to replicating Illumina's success." "Ginkgo Bioworks, Inc. (founded 2008), 10x Genomics (2012), and Twist Bioscience (2013) were born into an era of easy money. They were built like it, too. PacBio (2004) is spiraling toward bankruptcy, whether investors realize it or not, primarily because it never prioritized operating efficiency in its two-decade history. It shows, too." "If adversity breeds resilience, and resilience breeds profitable operations, then some of the world's most efficient businesses ever created are forming right now during biotech's current funding crunch." [👏👏👏] "We just can't appreciate it yet. We don't even know the names of many of these companies. Some primordial teams are meeting right now, reading this, and about to launch a motherfucker of a business. Good." [👏👏👏]

288

17 Comments