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To avoid ILD, we designed M9140 by conjugating the maleimide-containing hydrophilic \u03b2-glucuronide linker to exatecan and our anti-CEACAM5 (CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 5) specific antibody. Following repeated iv-infusion at 3 to 30\u00a0mg\/kg of M9140 every 3 weeks, the pathological findings obtained in cynomolgus monkeys were confined to gastrointestinal and hematolymphoid tissues and resembled the toxicity of exatecan. At 24\u00a0mg\/kg or higher, transient reductions in neutrophil and reticulocyte counts were observed with each dosing event along with reversible anemia throughout the study. The no observed adverse effect level was 24\u00a0mg\/kg and the maximum tolerated dose was 30\u00a0mg\/kg. The difference in toxicity by this small dose increment was correlated with a 2.5-fold difference in plasma exatecan exposure indicating antigen-independent toxicity. As anticipated, no lung toxicity was found with M9140 in these studies that were similar in study design to those used to confirm ILD with trastuzumab-deruxtecan in monkeys. Since the non-human primate model is regarded as predictive for the ILD risk in humans, this result indicates a low risk for ILD when applying M9140 to patients. The current M9140 safety data are discussed with special focus on the absence or presence of ILD with other antibody camptothecin-conjugates, for which a hypothetical pathogenic mechanism is postulated here. The favorable nonclinical profile of M9140 warrants further investigation in patients with CEACAM5-overexpressing tumors.<\/jats:p>","DOI":"10.1177\/10915818241306039","type":"journal-article","created":{"date-parts":[[2025,1,4]],"date-time":"2025-01-04T06:01:42Z","timestamp":1735970502000},"page":"153-169","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["The Nonclinical Safety Assessment of a Novel Anti-CEACAM5 Antibody Exatecan Conjugate Predicts a Low Risk for Interstitial Lung Disease (ILD) in Patients\u2014The Putative Mechanism Behind ILD"],"prefix":"10.1177","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2420-4732","authenticated-orcid":false,"given":"Willem N.","family":"Sloot","sequence":"first","affiliation":[{"name":"Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Bertotti","sequence":"additional","affiliation":[{"name":"Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany"},{"name":"CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche \u201cAntoine Marxer\u201d \u2013 RBM, Colleretto Giacosa (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Onidi","sequence":"additional","affiliation":[{"name":"Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany"},{"name":"CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche \u201cAntoine Marxer\u201d \u2013 RBM, Colleretto Giacosa (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Paoletti","sequence":"additional","affiliation":[{"name":"Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany"},{"name":"CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche \u201cAntoine Marxer\u201d \u2013 RBM, Colleretto Giacosa (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse De","family":"Salve","sequence":"additional","affiliation":[{"name":"Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany"},{"name":"CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche \u201cAntoine Marxer\u201d \u2013 RBM, Colleretto Giacosa (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Tavano","sequence":"additional","affiliation":[{"name":"Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany"},{"name":"CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche \u201cAntoine Marxer\u201d \u2013 RBM, Colleretto Giacosa (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Vigna","sequence":"additional","affiliation":[{"name":"Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany"},{"name":"CPS (Clinical and Pre-Clinical Safety) and NBE-DMPK (New Biological Entity - Drug Metabolism and Pharmacokinetics), Istituto di Ricerche Biomediche \u201cAntoine Marxer\u201d \u2013 RBM, Colleretto Giacosa (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gundi","family":"Mueller","sequence":"additional","affiliation":[{"name":"Chemical and Preclinical Safety Department, Global Chemical and Preclinical Safety, Merck KGaA, Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,1,4]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","unstructured":"Modi S Saura C Yamashita T etal. 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