Aaron Ring

T cells do the heavy lifting when it comes to the anti-tumor action of checkpoint immunotherapy. But do antibodies play a role too? That’s the question @yile_dai looked to answer in his thesis work, out today in @Nature! 🧵below nature.com/articles/s4158…

@kansagraMD @HiraSMian @RahulBanerjeeMD @HadidiSamer @rajshekharucms @Rfonsi1 @DrRakeshPopat @bdermanmd Is this seen with CAR-T as well?

This is a challenge due to BCMA affinity IMO We know BCMA is identified on myelin producing Schwann cells, and certain cranial/peripheral along with BG If you look at affinity of bcma in tec and linvo; they are in sub-nano molar and in Elra it’s low nano molar. (I will have to dig exact no), and all those could add up to likely toxicity and give us avenues to manage these .

HR SMM, "peripheral neuropathy (20%), mostly grade 1–2 and 1 case of GBS". This seems really high for a patient population that has not received any prior treatment....Grade 1/2 neuropathy can have unporportional impairement on QoL.

@cremieuxrecueil Honestly I would rather take inclisran q 6 months than permanent gene editing with current tech.

Eli Lilly has done it. They've gone and made what seems to be a powerful, permanent gene therapy for LDL cholesterol. That means they'll be able to effectively prevent most heart disease with a single infusion!

@dgermain21 I don't think we captured this one in our structure paper, but we can toss this antibody into an upcoming reap run sometime in the future.

@aaronmring A specific anti-BCMAxCD3 TCE causing GBS-like EMG/NCS changes...is it the unique anti-BCMA scFv being used? Could an off-target issue be mapped?

@dgermain21 👀

Another banger from @ChoYehlin !

@ATinyGreenCell Can you clone as zerg or protoss? This is important to me.

Excited to say I'll be releasing version 1.0.0 of SpliceCraft in just 4 days time! It won't be perfect, but I have done as much as I could to bring it to this state and will be open to all criticism on the behavior, utility, errors, etc. Let ego not be the death of good tooling.

@design_proteins dude that is lit. Can you post the prompt or create a skill?

PD1-PDL1 binding viz made with claude code

@SamDavisEsq @PearlF @ablT315I @damiangarde For mAbs, "best in class" is usually cope. Look at PD1 for example. They are all virtually the same. First is best in some cases. I agree it's a stretch, but the investor's point is directionally right. Things cost half as much and get done twice as fast in China.

@aaronmring @PearlF @ablT315I @damiangarde Best In Class They said

A US-based biotech VC told @damiangarde: "you can spend $10 million on a best-in-class drug from China, or you can hire 25 people in the US & pay them some $40 million over 3 years to get to the exact same point. In general, going with China works out to a roughly 50% cost savings, he said, meaning the same monetary investment can fund double the work."

@SamDavisEsq @PearlF @ablT315I @damiangarde For a vanilla mAb it's reasonable for a tier 1b/tier 2 Chinese CDMO.

@aaronmring @PearlF @ablT315I @damiangarde You’re being generous but even if I go along with this - the $10M figure for discovery deal is not grounded in reality

@PearlF @ablT315I @damiangarde Probably referring to using a CRO/CDMO to do the discovery/development work on a new asset, not buying an existing asset.

@ablT315I @damiangarde Is it just $10M to buy a "best-in-class" drug from China? What about the deals announced where some Chinese companies are getting 100's of millions in upfront money from biopharmas?

Very excited to get this new work by Shin Ngiow up on #bioRxiv. We may be blocking PD-1 too long causing detrimental effects on Tpex cells. A drug holiday approach may be beneficial. Also some cool new Tpex biology here. #immunopharmacology biorxiv.org/content/10.648…

@tejada444 @Biohazard3737 IL-18 is not essential for tumor immune surveillance. The classic Schreiber-esque studies didn't show an impact. In fact, IL-18 pathway knockouts are generally pretty subtle from an immunodeficiency standpoint. Nevertheless, I have long thought IL-18 agonism is a good idea. 😅

@ilyassahinMD It was a great idea, but the company Vor dropped the program and pivoted to I&I. The GO data is cool, but probably not cost-efficacious commercially. They were pursuing a CD33 CAR-T (VCAR33) but with 2 cell therapies (Trem-cel + VCAR33) it was probably >$1m/patient. $$$ phase 2/3

*nature.com/articles/s4159…

Another creative idea in cancer therapy lately... A new @NatureMedicine * study transplanted CRISPR-edited donor stem cells with CD33 removed into patients with high-risk AML. Because the new marrow lacks CD33, a CD33-targeted drug (gemtuzumab) can then wipe out residual leukemia without harming the healthy donor cells.✅ All 30 patients engrafted (median 10 days). Relapse-free survival 14 months in a population where outcomes are usually much worse. Still early and intensive, but the idea is exciting: engineering normal tissue so cancer therapy can be more selective and safer.

@ImmunoFever I would take this over plasma any day of the week.

@aaronmring I totally agree with you that there should be a path towards quick access for exposed individuals and their contacts where speed could quench an entire outbreak before further spread. Is it quicker if patient derived antibodies get a category closer to convalescent plasma use?

We need a more nimble regulatory framework for outbreaks like hantavirus. There is already a compelling therapeutic candidate: a human mAb isolated from a recovered patient, with strong preclinical activity against the Andes variant. Yet access remains months to years away.

@ChildrenNeedUs_ Not a virologist, so I can't say how "good" these models are considered. But the antibody I'm referring to was tested preclinically in Syrian hampsters: pmc.ncbi.nlm.nih.gov/articles/PMC11…

@aaronmring Is there a really good snimal model for HantaVirus? For SarsCov2 ,if you remember, work on Syrian hamsters just about perfectly translated to humans. I would have felt very comfortable taking a medicine that had only been tested in the hamsters.

In any case, patient-derived mAbs like this are a special category. They have, in a limited but meaningful sense, passed a “clinical trial of nature”: they existed in a human survivor, were tolerated, and were plausibly protective.

We use this type of lab grade material for high-stakes preclinical studies, including non-GLP NHP studies, all the time. For mAbs, manufacturing impurity is rarely the dominant risk. In a lethal outbreak, the dominant risk is the virus.