Aethon Therapeutics’ Post

A recently published paper describes preclinical results for CTX-8371, a protein construct that combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. Developed by Compass Therapeutics Inc., it is composed of an anti-PD-1 aglyco-IgG1 with the Fab of anti-PD-L1 (heavy + light chain) fused at the C-terminus of each of its heavy chains through a glycine-serine (G4S)4 linker. Investigations into the activity of CTX-8371 revealed a mechanism of action not previously described for PD-1 or PD-L1 CPIs, namely the bispecific antibody-induced proteolytic cleavage of cell surface PD-1. A Phase 1 (NCT06150664), first-in-human study of CTX-8371 administered as a monotherapy in patients with metastatic or locally advanced malignancies is due to start soon. #mabs https://lnkd.in/eSn97Xd5

Glad to see our B-hPD-1/hPD-L1 mice (https://lnkd.in/ejuMX3DA) supporting the discovery of novel immune-checkpoint drugs! #mousemodel #preclinicalresesarch #therapeutics #immunotherapy  #immunooncology #drugdiscovery #pharmacology #immunecheckpoint #tumormodel

Glad to see our B-hPD-1/hPD-L1 mice (https://lnkd.in/ejuMX3DA) supporting the discovery of novel immune-checkpoint drugs! #mousemodel #preclinicalresesarch #therapeutics #immunotherapy  #immunooncology #drugdiscovery #pharmacology #immunecheckpoint #tumormodel

In a recently published paper, Roche authors and colleagues report an experimental platform to de novo identify interactomes of TCR-like antibodies directly in human tissues using mass spectrometry. From the abstract: As proof of concept, we confirm the target epitope of a MAGE-A4-specific TCR-like antibody. We further determine cross-reactive peptide sequences for ESK1, a TCR-like antibody with known off-target activity, in human liver tissue. We confirm off-target-induced T cell activation and ESK1-mediated liver spheroid killing. Off-target sequences feature an amino acid motif that allows a structural groove-coordination mimicking that of the target peptide, therefore allowing the interaction with the engager molecule. We conclude that our strategy offers an accurate, scalable route for evaluating the non-clinical safety profile of TCR-like antibody therapeutics prior to first-in-human clinical application. #mabs https://lnkd.in/ewmXUzDF

Among future developments in the ADC field, payload diversification is expected to play a key role as illustrated by a growing number of preclinical and clinical stage unconventional payload-conjugated ADCs. This review presents a comprehensive overview of validated, forgotten and newly developed payloads with different mechanisms of action. The first and corresponding author of this excellent open access review article is Louise Conilh who used to be a graduate student at University of Lyon. Louise Conilh is currently a senior manager at Mablink Bioscience, a French ADC biotech company acquired last year by Eli Lilly and Company. By the way, Antibody Therapeutics (2023 CiteScore: 8.7), the officially journal of Chinese Antibody Society, published by Oxford University Press, calls for paper in “Antibody-Drug Conjugates for Cancer Treatment”. You are welcome to submit your ADC manuscripts for this special collection by August 31, 2024. You may know more detailed information from the link below to the website of call for papers announcement. https://lnkd.in/g_Ck_q2z #antibodies #antibody #antibodytherapeutics #mabs #mab #antibodydiscovery #adc #adcs #antibodydrugconjugates #antibodydrugconjugate #payloads

Mixed Lymphocyte reaction (MLR) assay : The MLR assay serves as a critical tool in biopharma, providing insights into the complex interactions of immune cells. By assessing cellular proliferation and cytokine secretion, MLR aids in evaluating the immunomodulatory effects of potential therapeutics. Its customizable nature allows biopharma companies to tailor experiments, accelerating the development of novel immunomodulatory drugs. BioRadius is a premier CRO specializing in supporting preclinical in vitro immuno-oncology endeavors. Our diverse assay portfolio encompasses mixed lymphocyte reaction assay (MLR), Antibody-dependent cellular cytotoxicity (ADCC), custom T-cell activation bioassays, MLR, and Immune mediated tumour killing assays. These assays are tailored to your unique requirements, offering comprehensive insights to navigate early-stage drug development confidently. Collaborate with BioRadius to unlock the potential of your immuno-oncology innovations and expedite the path to groundbreaking cancer therapies. #MLRassay #biosimilars #Tcellassays #immunooncology #invitro cell based assays #ADCC #biopharmaceuticals

The authors present a strategy for targeted protein degradation in a specific cell type. The approach involves designing and synthesizing a trastuzumab-PROTAC conjugate (Ab-PROTAC 3). This conjugate utilizes an antibody linker to mask E3 ligase-directed degrader activity, which is subsequently hydrolyzed upon internalization of the antibody–PROTAC complex. This process releases the active PROTAC, enabling catalytic degradation of targeted proteins. Specifically, they demonstrate that '3' selectively degrades bromodomain-containing protein 4 (BRD4) exclusively in HER2-positive breast cancer cell lines, while sparing HER2-negative cells. Through live cell confocal microscopy, they observe internalization and lysosomal trafficking of the conjugate specifically in HER2-positive cells, leading to sufficient release of active PROTAC and potent BRD4 degradation. These findings establish proof-of-concept for achieving tissue-specific BRD4 degradation, addressing challenges associated with PROTAC selectivity and offering promising avenues for targeting novel proteins.

They write: Here, we describe a strategy for selective protein degradation in a specific cell type. We report the design and synthesis of a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) in which E3 ligase-directed degrader activity is caged with an antibody linker which can be hydrolyzed following antibody–PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation. We show that 3 selectively targets bromodomain-containing protein 4 (BRD4) for degradation only in HER2 positive breast cancer cell lines, while sparing HER2 negative cells. Using live cell confocal microscopy, we show internalization and lysosomal trafficking of the conjugate specifically in HER2 positive cells, leading to the release of active PROTAC in quantities sufficient to induce potent BRD4 degradation. These studies demonstrate proof-of-concept for tissue-specific BRD4 degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.

Programmable Drug Delivery -iPRECIO Programmable Minipumps for better Predictivity in Oncology Programs. Selected highlights - Peer Reviewed publication and 2 webinars. SMP-310R " These findings demonstrate that antitumor activity can be achieved under both q.d. and b.i.d. dosing. To better understand the relationship between PK, target occupancy, and efficacy, a continuous infusion xenograft study was performed in the LU99 xenograft model and the PK/TO model applied to estimate the resulting levels of KRAS(G12C) target occupancy. " from Weiss, Andreas, et al. "Discovery, preclinical characterization, and early clinical activity of JDQ443, a structurally novel, potent, and selective covalent oral inhibitor of KRASG12C." Cancer Discovery 12.6 (2022): 1500-1517. https://lnkd.in/d8WnjtCj SMP-300/SMP-310R “Non-clinical program in rodents. We evaluated PK, efficacy, and tolerability of continuous lenalidomide compared to once-a-day intraperitoneal delivery of lenalidomide.” “To provide the continuous infusion of lenalidomide we used a iPRECIO pump.” Starton Therapeutics- Precision Blood Cancer Conference September 2021 https://lnkd.in/gursrxAT with Jamie Oliver SMP-310R & SMP-200  Unprecedented PK-PD correlations in-Vivo Pharmacology Learn how christian schnell, Associate Director Oncology NIBR, Novartis Pharma AG, Basel, CH reached his conclusions. Now available on demand. Expert Answers, Q&A Report Slide Deck, and On-demand Webinar< https://lnkd.in/eZNQNPdn #oncology #drugdelivery #drugdevelopment #PKPD #preclinical

We will present at the PBSS-San Francisco Bay Symposium: Innovative Life Science Technologies in the Drug Development Toolbox: From Cancer Organoids and Biomarker Profiling to Label-Free Multiplex QES Assays The abstract of this symposium: The era of one-size-fits-all pharmaceuticals is fading. Today, the drug development landscape brims with groundbreaking modalities - from gene and cell therapies to mRNA and antibody-drug conjugates (ADCs) armed with radiotherapy. This transformative journey demands equally disruptive tools to streamline and accelerate research. Join us at this symposium as we explore the frontier of technology propelling the discovery of next-generation therapeutics. This symposium will showcase a diverse arsenal of tools designed to empower every stage of drug development. Topics include single-cell analysis, AI-based protein design, cancer organoids for drug screening, multiplex assays sans detecting agents, and sensitive NGS/multiomic biomarker profiling assays revealing previously hidden disease complexity. These advancements reflect the continuous pursuit of innovation, accelerating the quest for more effective, targeted, and ultimately, transformative therapeutic solutions. Registration and Agenda link: https://lnkd.in/gY8gy-jQ