Ian Scott, PhD, FRSC, CChem

For anyone building diagnostics: Very cool approach to gain valuable insights into FDA decision summaries. Brendan O'Leary scraped the FDA’s decision summaries and provided some simple R code for anyone to get up and running in no time to prod and probe those summaries. Very nice work!

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Dr. Nina E. Weisser, Director of Preclinical, Multispecific Antibody Therapeutics, recently authored an article published in Drug Target Review discussing the development of trispecific T cell engagers (TriTCEs) with integrated CD28 costimulation. TriTCEs are designed to address the limitations of conventional bispecific TCEs in treating solid tumors by providing balanced T cell activation, leading to potentially more sustainable anti-tumor responses. This innovative approach could significantly advance immunotherapy for patients with difficult-to-treat solid tumors. Access the article: https://lnkd.in/ewRJvPA9

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Want glycan analysis method expertise? In this video, our Navin Rauniyar discusses his recently published study. Check it out! #proteinsciences #protein #groundbreaking #biotech #CDMO #analyticaldevelopment #glycananalysis

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A nice commentary on our paper, published this month in the September issue of Cancer Discovery https://lnkd.in/gD24f8zn 

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QPS Holdings, LLC is a #Global #Industry #FullService #CRO leader in #CELL and #GENE #Therapy from our #lab and #translationalmedicine services --> #FirstInHuman #FirstInMan #Phase1 --> #Phase1b,#Phase2 and #Phase3 #clinical #studies. Trust over 25 years of experience taking your asset from #preclinical to #clinical in the #USA, #Europe and #Asia. When #Quality and #Experience matter trust QPS... why use multiple vendors and #CRO,#CDMO. #CustomBuiltResearch

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Engineered CD47 protects T cells for enhanced antitumour immunity Adoptively transferred T cells and agents designed to block the CD47–SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a ‘don’t eat me’ signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours. https://lnkd.in/eUsVmmw2

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Bristol Myers Squibb has queued a Phase 1 study of Orum Therapeutics’ ORM-6151 (BMS-986497), a first-in-class, anti-CD33 antibody-enabled GSPT1 degrader for the treatment of patients with acute myeloid leukemia or high-risk myelodysplastic syndromes. The study will enroll an estimated 35 patients and is due to start in late May 2024. Orum Therapeutics has developed a new class of ADC payloads, called neoDegraders, to specifically degrade intracellular target proteins within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, neoDegraders are designed to be delivered specifically to cancer cells and degrade the intracellular target protein and cause tumor cell death. https://lnkd.in/edTcDRFj

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#ASH24 The mRNA-based T cell engager targeting BCMA, FcRH5, and GPRC5D is not a trispecific TCE. Instead, BCMA×CD3, FcRH5×CD3, and GPRC5D×CD3 are translated as separate bispecific proteins. Moderna

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Acurx Pharmaceuticals Announces Presentation of Ibezapolstat Phase 2 Clinical Trial Results for CDI at Scientific Conference   • Additional analyses of clinical and microbiological data from the Phase 2b segment show favorable gut microbiome changes including increased relative proportion of Actinobacteria in ibezapolstat-treated patients with C. difficile Infection (CDI) • Results consistent with those shown in earlier human volunteer studies and Phase 2a studies • Preservation and increased concentrations of beneficial Firmicute (Bacilotta) phylum known to be involved in bile acid homeostasis and short chain fatty acid metabolism was demonstrated  • Actinobacteria and Bacteroides preservation also confirmed using quantitative analysis   https://lnkd.in/eseFt8GZ   #nasdaq #acxp #antibiotics #acurx Acurx Pharmaceuticals, Inc. (Nasdaq: ACXP) David Luci

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Although several CD137 agonistic antibodies, mainly T cell engagers, are in clinical development, biomarker understanding remains limited. Compass Therapeutics Inc.’ corporate update indicates that a Phase 2 trial of CTX-471—a CD137 agonistic antibody targeting tumors expressing neural cell adhesion molecule (NCAM, or CD56)—is planned for mid-2025. Phase 1 trial data presented in the SITC24 poster, derived from tissue and blood sample analyses, reveal CTX-471’s unique mechanism. CD56 interactions between tumor cells and NK cells enhance NK cell infiltration into the tumor microenvironment. Once inside, NK cell-expressed CD137 (4-1BB) binds to CTX-471, triggering robust immune activation. Highly intriguing potential mechanism. https://lnkd.in/gY5_Et7p https://lnkd.in/gDYXk82P

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The past two days have witnessed two Nobel Prize awards to machine learning and artificial intelligence. Kudos to Geoff Hinton, John Hopfield, David Baker, Demis Hassabis and John Jumper for their amazing contributions. In chemistry, the story of AI/ML goes back to Corwin Hansch and Toshio Fujita (1962), who started the field of QSAR. Fun fact (Alicia Higueruelo and Jordi Mestres can confirm): At #EuroQSAR in Barcelona, on September 27, I openly stated that Jumper & Hassabis are strong contenders for the Nobel prize. At least one prediction from that conference proved to be accurate. Back to this Editorial (once again, thank you Craig Lindsley, Ph.D., FRSC, FASPET, FAAS, FNAI). I am glad it got published "as is", with very minor modifications from May 2003. Indeed, the text and references have not been modified since. To paraphrase one of David Weininger's friends, Douglas Adams, "[chemical] Space is big. Really big. You just won't believe how vastly, hugely, mind-bogglingly big it is. I mean, you may think it's a long way down the road to the chemist's, but that's just peanuts to space" . Chemists will need computers & AI to navigate that really big chemical space. Note to non-UK English speakers: chemist == pharmacist in this instance.

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FDA Guidance on CGT Products: A New Era for Regulatory Clarity? The FDA’s draft guidance on CGT products is a critical resource for sponsors. It offers clear expectations for IND submissions, expedited pathways, and product characterization. Our team sees this as an opportunity for sponsors to take a more proactive approach with regulators - especially through early meetings like INTERACT and pre-IND. But we know the execution isn’t always straightforward. What are your thoughts on the guidance? Are you seeing clearer pathways, or do the hurdles remain? 👉 Access the guidance here: https://lnkd.in/eQbNpvJK #FDA #CGT #CellTherapy #GeneTherapy #INTERACT #preIND

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A novel case of BiTE (EGFRxCD28) plus anti-PD-1: Targeting the 'right' patients counts! Colon cancer with microsatellite stability (MSS), 85% of patients¹, is non-responsive to anti-PD-1 therapy²⁻³. Recently, REGN7075, a EGFRxCD28 BiTE, plus anti-PD-1 showed encouraging efficacy, 6% (3/51) objective response rate (ORR); moreover, all responders were non-metastatic patients. Among the subset of non-metastatic patients (15), ORR became 20% (3/15)³. This validated our proposal that BiTE or anti-PD-1 or duo is more applicable to early-stage non-metastatic, instead of late-stage metastatic, solid-tumour cancer patients (see recent POSTs). The wild-type (WT) EGFRs are expressed on normal and cancer cells⁴, and colon cancer expresses WT EGFR⁵. A novel EGFR mAB targeted the epitope in Domain II (CR1) of extracellular domains⁵. The Domain II is masked in quiescent EGFRs of normal tissues, yet is exposed in EGFRs of cancer cells⁵. We deduced that REGN7075 also targeted the epitopes in Domain II, resulting in minimal on-target off-tumour toxicity of normal cells. TGN1412, a CD28 mAB, induced severe cytokine release syndrome⁶ (CRS); however, a novel CD28 mAB had shown lower CD28 affinity by targeting the epitope near the apex, instead of TGN1412's targeting the lateral epitope near cell membrane⁷. We deduced that REGN7075 also targeted the epitope near the apex of CD28, resulting in low CRS rate. By targeting novel epitopes of EGFR & CD28 presumably, REGN7075 incurred 35% of patients with grade 3/4 adverse events³ vs typical BiTE's 62-87%⁸⁻⁹. The CD3-based BiTE mimics signal 1 for T-cell activation by binding CD3. The CD28-based BiTE mimics signal 2 by binding the costimulatory CD28 receptor (ligands: CD80/86). The 'functional' DCs have become rare in tumour milieu and tumour itself does NOT emit danger signals to activate these rare DCs for upregulating CD80/86. Thus, there is the scarcity of CD80/86 (signal 2) in tumour milieu for properly 'reactivating' subprimed PD-1⁺ tumour-infiltrating T cells, which were initially 'subprimed' in lymph nodes by only signal 1 (see recent POSTs). By using anti-PD-1 (low dose) for T-cell 'reactivation'¹⁰ as signal 1 and CD28-based BiTE for direct CD28 binding as signal 2, the sub-primed PD-1ˡᵒʷ⁻ᶦⁿᵗ CD8⁺ T cells can resume cytotoxic effector function (granzymes and perforin) to kill tumours. Thus, Regeneron's novel duo of CD28-based BiTE plus anti-PD-1 is an encouraging therapy for early-stage non-metastatic colon cancer patients with MSS. 1. Brenner, Lancet, 2014 2. Lin, Cancer Immunol Immunother, 2023 3. https://lnkd.in/gH876tXN 4. S Khaznadar, Oncotarget 5. Gan, Cancer Res, 2012 6. S Suntharalingam, New Engl J Med 7. A Elsayed, MABS 8. Dickinson, New Engl J Med, 2022 9. Kantarjian, New Engl J Med, 2017 10. T Elliot, Immunity #Immunotherapy #ImmunoOncology #BiTE #PD1 #Costimulation #Pharmaceutical

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Great example from Novartis on leveraging several hit finding technologies (e.g., fragment and DNA-encoded libraries, peptides, and virtual screening) to find new binders to different sites on IL1β cytokine that disrupt the interaction with IL1R1 receptor. The team identified IL1β lysine K103 as a target residue suitable for the development of covalent IL-1β/IL1R modulators. #drugdiscovery #covalency

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Highlights the importance of taking biophysical properties into consideration in designing novel TKIs. FGFR2 specificity vs. FGFR1. Very cool findings in PNAS.

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