Drug addiction Antibacterial agents Allergy Covalent drugs
Monoclonal Explainable deep Eliminating IgE High-throughput
antibody to treat learning discovers reverses allergy profiling of reactive fentanyl overdose novel antibiotic cysteines The opioid receptor antago- Deep learning approaches have Immunoglobulin E (IgE) plays An effective approach to target nist, naloxone, is currently the demonstrated success in identify- an essential role in type 1 disease-relevant proteins is the only available treatment for ing potential antibiotics from hypersensitivity reactions and use of covalent inhibitors that reversing the negative effects chemical libraries, but the mod- allergic disorders, representing engage nucleophilic cysteine resi- of fentanyl overdose, includ- els used are not explainable and a direct target to combat allergy. dues. Protein–ligand interactions, ing respiratory depression. do not provide chemical insight. However, complete elimina- including cysteine reactivity, However, naloxone cannot be Now, Wong et al. develop tion of pathogenic IgE produc- can be profiled using chemo- administered prophylactically, an explainable deep learning, tion has not yet been clinically proteomics techniques, such as and multiple administrations substructure-based approach achieved. activity-based protein profiling are typically necessary. for the discovery of novel anti Here, Limnander et al. (ABPP) technologies. However, Here, Bremer et al. profile the biotics. First, a set of 39,312 chem- present a strategy designed adapting proteome-wide profil- opioid binding activity of ically diverse compounds were to both eliminate existing ing of cysteine ligandability for the fully human monoclonal screened for growth-inhibitory IgE-producing plasma cells high-throughput applications antibody (mAb) CSX-1004, activity against S. aureus. Using (PCs) and prevent the forma- remains challenging. designed to bind fentanyl. The Chemprop, ensembles of graph tion of new IgE-producing PCs. Here, Yang et al. present mAb recognized a wide range of neural networks were trained They harness their previously a multiplexing-based high- fentanyl analogues (FAs) with on the screening data to predict developed bispecific antibody throughput platform in 96-well picomolar affinity and did not whether a new compound will BCMAxCD3 — which binds B cell plates, called tandem mass tag cross-react with endogenous inhibit bacterial growth based maturation antibody (BCMA) (TMT)-ABPP, for proteome-wide opioid peptides, prescription on its chemical structure. This on PCs through the targeting profiling of reactive cysteines. opioids, or opioid antagonists. training set of compounds was arm, and CD3 on T cells through TMT-ABPP enables routine inter- In mice administered fentanyl counter-screened for cytotoxic- the effector arm — to induce rogation of 18,000 or 24,000 to induce a near maximal possible ity in three human cell lines, to T cell-mediated killing of PCs. reactive cysteines based on only effect, intravenous CSX-1004 develop orthogonal models that This antibody is combined with 10 or 20 μg of native proteome markedly reversed fentanyl- predict cytotoxicity. dupilumab, which blocks IL-4Rα input, respectively. Compared induced antinociception within The trained graph neural to inhibit IgE class switching. to existing strategies, this 20 minutes. The mAb also networks were applied to make Importantly, this approach platform provides a 2–3 fold improved respiratory depression predictions of antibiotic activity allows for reconstitution of improvement in cysteinome induced by carfentanil (a potent and cytotoxicity for 12,076,365 other immunoglobulin classes. coverage and a 5–10 fold FA) within 10 minutes, surpassing compounds. Explainable In a mouse house dust mite reduction in input material. the magnitude of naloxone rever- graph algorithms identified exposure model of allergy, Applying the TMT-ABPP sal within 60 minutes of treat- substructure-based ration- transient depletion of PCs with platform to screen a library of 192 ment. In addition, pretreatment ales for compounds with high BCMAxCD3, combined with sus- electrophiles in HEK293T cells, of mice with CSX-1004 prevented predicted antibiotic activity tained IL4Rα blockade, ablated the researchers mapped the ligan- fentanyl antinociception. In rats, and low predicted cytotoxicity. IgE production and blocked IgE dability of more than 38,000 reac- CSX-1004 displayed a favourable Filtering steps resulted in a set resurgence, preventing anaphy- tive cysteines from 8,274 human pharmacokinetic and toxico- of 283 compounds, which were laxis upon allergen re-exposure. proteins, creating the largest logical profile. In a non-human experimentally tested. Two Similarly, persistent elimina- coverage of reactive cysteinome primate model of opioid-induced compounds from the same struc- tion of IgE was obtained using within a single cell line. respiratory depression, CSX-1004 tural class were selective against the combination treatment in The improved sensitivity significantly antagonized the methicillin-resistant S. aureus cynomolgus monkeys. Further- of the TMT-ABPP platform effects of repeated fentanyl (MRSA) and vancomycin-resistant more, the bispecific antibody revealed unknown cellular tar- challenges. enterococci, overcame common alone efficiently depleted gets of five well-characterized CSK-1004 infusion has resistance determinants, and IgE-secreting bone marrow PCs compounds and covalent entered phase I testing and were effective in both the topical from allergic donors in vitro drugs — ibrutinib, THZ1, has been granted fast track and systemic treatment of MRSA and completely reduced IgE in ARS-1620, Sulfopin, and DMF, designation by the FDA. in mouse infection models. patients with multiple myeloma. using three different cell lines. Sarah Crunkhorn Sarah Crunkhorn Sarah Crunkhorn Sarah Crunkhorn Original article: Bremer, P. T. et al. Original article: Wong, F. et al. Discovery Original article: Limnander, A. et al. Original article: Yang, K. et al. Accelerating Investigation of monoclonal antibody of a structural class of antibiotics with A therapeutic strategy to target distinct multiplexed profiling of protein-ligand CSX-1004 for fentanyl overdose. explainable deep learning. Nature https:// sources of IgE and durably reverse allergy. interactions: High-throughput plate-based Nat. Commun. https://doi.org/10.1038/ doi.org/10.1038/s41586-023-06887-8 (2023) Sci. Transl Med. 15, eadf9561 (2023) reactive cysteine profiling with minimal input. s41467-023-43126-0 (2023) Cell Chem. Biol. https://doi.org/10.1016/ j.chembiol.2023.11.015 (2023)
nature reviews drug discovery Volume 23 | February 2024 | 103–107 | 107
Active immunization to tumor necrosis factor-α is effective in treating chronic established inflammatory disease: a long-term study in a transgenic model of arthritis