International Journal of Toxicology最新文献

Effects of Solvent Dimethyl Sulfoxide Invites a Rethink of Its Application in Amyloid Beta Cytotoxicity. 溶剂二甲亚砜的作用引起对其在β淀粉样蛋白细胞毒性中的应用的重新思考。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-05-15 DOI: 10.1177/10915818251338235

Yanhong Fu, Jiafa Zhang, Canhong Yang, Yuanyuan Wang, Yunzhu Yang, Pingming Qiu, Weibing Xie, Shufen Zhang, Tianming Lǚ

{"title":"Effects of Solvent Dimethyl Sulfoxide Invites a Rethink of Its Application in Amyloid Beta Cytotoxicity.","authors":"Yanhong Fu, Jiafa Zhang, Canhong Yang, Yuanyuan Wang, Yunzhu Yang, Pingming Qiu, Weibing Xie, Shufen Zhang, Tianming Lǚ","doi":"10.1177/10915818251338235","DOIUrl":"https://doi.org/10.1177/10915818251338235","url":null,"abstract":"Dimethyl sulfoxide (DMSO) is commonly used as a solvent for preparing amyloid-beta (Aβ) peptides implicated in Alzheimer's disease. While considered relatively non-toxic at low concentrations, DMSO itself may exert biological effects that could confound experimental outcomes, especially for weakly cytotoxic substances like Aβ. Seven brain cell types (BV-2, N2a, SH-SY5Y, U87, neurons, astrocytes, microglia) were treated with varying DMSO concentrations or Aβ1-42 oligomers/protofibrils/fibrils prepared using DMSO. Cell viability was assessed by CCK-8 and LDH assays. Matched DMSO controls were prepared alongside Aβ treatments to delineate solvent effects. Low DMSO concentrations (0.0625-0.015625%) exhibited hormetic cytoprotective and growth-promoting effects, while higher concentrations (≥2%) were cytotoxic. Importantly, these hormetic solvent effects confounded the measurement of Aβ cytotoxicity. By accounting for matched DMSO controls, the study revealed that Aβ fibril toxicity may have been underestimated due to the cytoprotective solvent effects of low DMSO concentrations used in their preparation. In conclusion, DMSO exhibits complex hormetic dose-responses that can significantly influence experimental outcomes, especially for weakly cytotoxic agents like Aβ. Rigorous solvent controls are crucial to delineate genuine substance effects from potential solvent confounds and avoid erroneous interpretations.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251338235"},"PeriodicalIF":1.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safety Evaluation of N-trans-caffeoyltyramine Derived From a Strain of Yarrowia lipolytica Through Precision Fermentation. 一株解脂耶氏菌精发酵n -反式咖啡乙胺的安全性评价。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-05-07 DOI: 10.1177/10915818251338788

Sungwon Lee, Srinivas Seekallu, Suresh Babu Venkataramaiah, Chandrashekar Mataguru Doreswamy, Mohan Cheluru Umesh, Sandeep Malleshappa, Sajeev Justin Dev, Ganadhal Puttaramaiah Chethankumara, Nagaraju Lohith, Gajanan Rajpal Deshmukh, Brian Premkumar, Brinda Mahadevan

{"title":"Safety Evaluation of N-trans-caffeoyltyramine Derived From a Strain of Yarrowia lipolytica Through Precision Fermentation.","authors":"Sungwon Lee, Srinivas Seekallu, Suresh Babu Venkataramaiah, Chandrashekar Mataguru Doreswamy, Mohan Cheluru Umesh, Sandeep Malleshappa, Sajeev Justin Dev, Ganadhal Puttaramaiah Chethankumara, Nagaraju Lohith, Gajanan Rajpal Deshmukh, Brian Premkumar, Brinda Mahadevan","doi":"10.1177/10915818251338788","DOIUrl":"https://doi.org/10.1177/10915818251338788","url":null,"abstract":"N-trans-caffeoyltyramine (NCT) is a phenolic hydroxycinnamic acid amide naturally present in many plant crop species and is associated with immune response and many development processes. Little research has been done on the potential safety of NCT for use as an ingredient in conventional foods and beverages. This study assessed the safety of NCT derived from caffeic acid and produced using a genetically engineered strain Yarrowia lipolytica strain 3599_7 via precision fermentation through in vitro genotoxicity assays and a 90-day dietary oral toxicity study in rats. The Ames test was performed in bacterial strains and the highest dose tested was 5000.0 μg/plate in the presence and absence of S9. The in vitro mammalian micronucleus test was conducted in human peripheral blood lymphocytes in culture exposed to NCT at predetermined concentrations in the absence (4-hour and 24-hour exposure) and presence (4-hour exposure) of S9. NCT was not genotoxic as evident from the Ames and the in vitro micronucleus assay. NCT exhibited no adverse effects in the 90-day oral toxicity study up to the highest dose tested, where the no-observed-adverse-effect level was 1427 and 1983 mg/kg body weight/day in males and females, respectively.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251338788"},"PeriodicalIF":1.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of In Vitro Toxicity of OrPhyllo™, a New Vehicle to Produce Orodispersible Films. 制备多孔分散膜的新载体OrPhyllo™体外毒性评价

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-05-06 DOI: 10.1177/10915818251340384

Hudson Polonini, Bruna Marianni, Emanuel da Silva Rovai, Maria Aparecida Neves Jardini, Camilla Magnoni Moretto Nunes, Carlos Rocha Oliveira

{"title":"Evaluation of In Vitro Toxicity of OrPhyllo™, a New Vehicle to Produce Orodispersible Films.","authors":"Hudson Polonini, Bruna Marianni, Emanuel da Silva Rovai, Maria Aparecida Neves Jardini, Camilla Magnoni Moretto Nunes, Carlos Rocha Oliveira","doi":"10.1177/10915818251340384","DOIUrl":"https://doi.org/10.1177/10915818251340384","url":null,"abstract":"Orodispersible films (ODFs) are advanced drug delivery systems that consist of thin, mechanically robust polymeric films designed to dissolve or disintegrate quickly in the oral cavity, facilitating local and systemic drug administration. Orphyllo™ is a novel ODF vehicle developed to enhance the stability and delivery efficiency of active pharmaceutical ingredients. This study aimed to assess the safety profile of Orphyllo™ through a comprehensive evaluation of its cytotoxicity and genotoxicity on human oral mucosa cell lines. The cytotoxicity was evaluated using (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) MTT, Neutral Red Uptake (NR), and Lactate Dehydrogenase (LDH) assays, which tested the impact of Orphyllo™ at concentrations of 5.0% and 10.0% over 24, 48, and 72 hours. Results indicated no significant reduction in cell viability (P > 0.05), demonstrating the formulation's biocompatibility. To evaluate genotoxicity, the micronucleus test was performed, showing no significant increase in the frequency of micronuclei compared to the control group, thus indicating no DNA damage. Additionally, the Annexin/7-AAD assay was employed to assess apoptosis and necrosis, revealing no significant induction of cell death at the tested concentrations (P > 0.05). These findings highlight that Orphyllo™ presents, even at an early stage, the potential to become a promising vehicle for oral drug administration applications, with potential benefits in several therapeutic areas, especially for populations that require ease of administration.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251340384"},"PeriodicalIF":1.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparative Analyses of the Influences of Vehicles on Selected Biological Parameters Following Single-Dose Oral Administration in Sprague-Dawley Rats. Sprague-Dawley大鼠单次口服载药对部分生物学参数影响的比较分析。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-04-22 DOI: 10.1177/10915818251330516

Tae-Woo Kim, Tae-Kyung Kim, Hye-Joon Park, Mu-Jin Lee, Sung-Jin Park, Laehong Jo, Yong-Hoon Lee, Yong-Seok Kim, Byeongwoo Ahn

{"title":"Comparative Analyses of the Influences of Vehicles on Selected Biological Parameters Following Single-Dose Oral Administration in Sprague-Dawley Rats.","authors":"Tae-Woo Kim, Tae-Kyung Kim, Hye-Joon Park, Mu-Jin Lee, Sung-Jin Park, Laehong Jo, Yong-Hoon Lee, Yong-Seok Kim, Byeongwoo Ahn","doi":"10.1177/10915818251330516","DOIUrl":"https://doi.org/10.1177/10915818251330516","url":null,"abstract":"Various types of vehicles are used in non-clinical studies to administer treatment substances to experimental animals. It is recognized that these vehicle substances can influence animal physiology to some extent. Studies are designed to minimize the effects of vehicle substances to ensure reliable results. However, research on the biological effects of these vehicles is still inadequate. This study aims to assess the effects of vehicles on selected biological parameters (body weight, food consumpton, water consumption, functional observational battery, clinical pathology, and organ weights) and to establish reference ranges for these parameters to aid in historical control data. A total of 1,528 Sprague-Dawley rats were used in this study, exposed to commonly utilized vehicles such as distilled water, corn oil, dimethyl sulfoxide (DMSO), polyethylene glycol 400, carboxymethyl cellulose, and methyl cellulose via oral dosing at 5 mL/kg body weight per day, consistent with the dosing regimen employed in the toxicity tests included in this study. Significant changes were observed in the red blood cell counts and organ weights with DMSO treatment, whereas other vehicles induced only minor changes. This study highlights the importance of careful vehicle selection in non-clinical trials to eliminate their biological impact.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251330516"},"PeriodicalIF":1.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Commentary: Looking Back and Looking Sideways. 评论：回顾与展望。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-04-09 DOI: 10.1177/10915818251328037

Anthony Dayan, Peter Pressman, Thomas Blackburn, Norbert Kaminski, Samuel Cohen, A Wallace Hayes

引用次数: 0

Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys. 静脉注射依曲帕米在有意识遥测食蟹猴体内的心血管和药代动力学特征。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-04-01 DOI: 10.1177/10915818251327963

Alexis Ascah, Jean-Pierre Moreau, Simon Authier, David B Bharucha, Douglas Wight

{"title":"Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys.","authors":"Alexis Ascah, Jean-Pierre Moreau, Simon Authier, David B Bharucha, Douglas Wight","doi":"10.1177/10915818251327963","DOIUrl":"https://doi.org/10.1177/10915818251327963","url":null,"abstract":"Paroxysmal supraventricular tachycardia (PSVT) is a common cardiac arrhythmia associated with substantial health care burden. Etripamil, a fast-acting non-dihydropyridine calcium channel blocker developed for intranasal self-administration, is currently under investigation for acute treatment of PSVT episodes. A novel two-phase study design was used to test a series of five doses of intravenous etripamil (0, 0.025, 0.05, 0.15, and 0.3 mg/kg) in conscious cynomolgus monkeys. The cardiovascular effects (e.g., blood pressure and ECG recordings) were assessed during the first phase, and the pharmacokinetic profile was characterized during the second phase. Animals were dosed remotely to avoid the stress of intranasal dosing and minimize the impact of dose administration on measurements. Results were compared with findings from subsequent intranasal studies in cynomolgus monkeys and humans. Etripamil decreased systolic blood pressure and increased heart rate proportionately in a dose-dependent manner. Etripamil also induced dose-dependent increases in the PR interval. At a dose of 0.3 mg/kg (the highest dose), the mean highest PR prolongation from baseline during 20 minutes after dosing was 27.38%. Systemic exposure to etripamil increased in a dose-dependent manner. Mean area under the curve from administration to when drug was no longer present (AUC0-∞) values ranged from 179 to 2364 ng • min/mL, peak plasma concentration ranged from 13.2 to 176 ng/mL, and mean half-life ranged from 12.3 to 20.8 minutes (Figure 1). Results were consistent with data from subsequent intranasal preclinical and clinical studies. Intravenous etripamil demonstrated the desired targeted pharmacokinetic and pharmacodynamic profiles in conscious cynomolgus monkeys.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251327963"},"PeriodicalIF":1.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin. 心脏肌球蛋白可逆变构抑制剂Aficamten的非临床药理学和毒理学研究。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-20 DOI: 10.1177/10915818251326466

Michael K Pugsley, Darren T Hwee, Brett R Winters, Jingying Wang, Eva R Chin, Bradley P Morgan, Fady I Malik

{"title":"A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin.","authors":"Michael K Pugsley, Darren T Hwee, Brett R Winters, Jingying Wang, Eva R Chin, Bradley P Morgan, Fady I Malik","doi":"10.1177/10915818251326466","DOIUrl":"https://doi.org/10.1177/10915818251326466","url":null,"abstract":"Aficamten (CK-3773274) is a cardiac myosin inhibitor in development for the treatment of hypertrophic cardiomyopathy (HCM), a commonly inherited heart condition often characterized as a disease of the sarcomere. Aficamten reduces pathologic cardiac hypercontractility by selectively binding to an allosteric site on cardiac myosin. To characterize the pharmacology and toxicology of aficamten, a series of nonclinical repeated dose studies were conducted. In a 10-day repeated dose pharmacology study in Sprague Dawley rats, aficamten produced dose-dependent reductions in left ventricular fractional shortening (FS) which were fully reversible within 24 h. Aficamten did not change the ratio of heart weight to tibia length (HW/TL) or left ventricular posterior wall (LVPW) thickness at any dose tested. At a supratherapeutic dose of 6 mg/kg/day, there was a significant increase in interventricular septum (IVS) thickness. Aficamten did not affect mRNA expression of the cardiac injury biomarkers BNP, β-MHC, or ANP. In repeated dose Good Laboratory Practice (GLP) regulatory toxicology studies in Sprague Dawley rats for up to 6 months and beagle dogs for up to 9 months, the primary adverse findings at supratherapeutic doses were consistent across all studies and observed in the heart consisting of atrial/ventricular dilatation that correlated with increased heart weights. These findings were largely reversible and consistent with excessive on-target pharmacology associated with cardiac myosin inhibition. The reversible nature of aficamten-associated adverse effects is supportive of its clinical safety as this property suggests that these findings, should they occur in humans, may also be reversible, limiting long-term human cardiac risk.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251326466"},"PeriodicalIF":1.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An Industry Perspective on the Use of Novel Excipients in Lipid Nanoparticles-Nonclinical Considerations. 在脂质纳米颗粒中使用新型赋形剂的行业前景-非临床考虑。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-04 DOI: 10.1177/10915818251320631

Lorrene A Buckley, Jessica E Sutherland, Prachi Borude, Karine Broudic, Philippe Collin, Aimee Hillegas, Chris MacLauchlin, Amer F Saleh, Amy Sharma, Justina Thomas, Matthew O'Brien Laramy

{"title":"An Industry Perspective on the Use of Novel Excipients in Lipid Nanoparticles-Nonclinical Considerations.","authors":"Lorrene A Buckley, Jessica E Sutherland, Prachi Borude, Karine Broudic, Philippe Collin, Aimee Hillegas, Chris MacLauchlin, Amer F Saleh, Amy Sharma, Justina Thomas, Matthew O'Brien Laramy","doi":"10.1177/10915818251320631","DOIUrl":"https://doi.org/10.1177/10915818251320631","url":null,"abstract":"Nucleic acid drug delivery with lipid nanoparticle (LNP) formulations has enabled the development of novel therapeutics and vaccines. LNP formulations are composed of both naturally occurring and synthetic lipid excipients. This perspective shares current practices in the nonclinical safety assessment of novel lipid excipients contained in LNP formulations and identifies gaps in current regulatory guidance on this topic. There is no globally harmonized regulatory guidance for the nonclinical safety assessment of novel excipients or guidance specific to safety testing of novel excipients in LNPs. Given the complexity of these LNP formulations, most nonclinical safety studies to support development are conducted with the drug product or with a LNP that contains non-active cargo. Three case studies (Onpattro®, Comirnaty®, and SpikeVax®) highlight that specific assessments may differ depending on the encapsulated modality, the intended use (e.g., therapeutic versus preventative vaccine), dose, and frequency of dosing. These case studies also suggest that regulatory agencies are open to scientific rationale to justify why certain tests should or should not be performed. As more products are approved, it will be important to understand how precedents set for approved products can be leveraged and what additional unique strategies may be applied to ensure nonclinical safety assessments are predictive, relevant, and meaningful for human safety. Proactive alignment with regulatory authorities will be critical in this context, especially as new approaches are proposed. Guidance documents may need to be revised or created as more experience is acquired to reflect the unique considerations for these novel excipients.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818251320631"},"PeriodicalIF":1.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Four-Week GLP Immunotoxicity Assessment of Lactoferrin Alpha Produced by Komagataella phaffii in Sprague-Dawley Rats. 在 Sprague-Dawley 大鼠体内对 Komagataella phaffii 产生的 Alpha 乳铁蛋白进行为期四周的 GLP 免疫毒性评估。

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-01 Epub Date: 2024-11-13 DOI: 10.1177/10915818241299344

Ross Peterson, Robert B Crawford, Lance K Blevins, Norbert E Kaminski, Anthony J Clark, Carrie-Anne Malinczak

{"title":"Four-Week GLP Immunotoxicity Assessment of Lactoferrin Alpha Produced by Komagataella phaffii in Sprague-Dawley Rats.","authors":"Ross Peterson, Robert B Crawford, Lance K Blevins, Norbert E Kaminski, Anthony J Clark, Carrie-Anne Malinczak","doi":"10.1177/10915818241299344","DOIUrl":"10.1177/10915818241299344","url":null,"abstract":"Oral toxicity and toxicokinetic properties of human lactoferrin (LF) alpha produced in Komagataella phaffii (effera™) were investigated in adult Sprague-Dawley rats over a 28-day period under good laboratory practice conditions. Main study dosing used groups of 10 rats/sex/dose, and a secondary study evaluating toxicokinetic parameters used 6 rats/sex/dose. The vehicle control group received sodium citrate buffer, test groups received daily doses of 200, 600, and 2000 mg of effera™ per kg body weight, and the comparative control group received 2000 mg bovine LF (bLF)/kg body weight per day. T-cell-dependent antibody response against keyhole limpet hemocyanin and immunophenotyping of the spleen were performed as measures of immunotoxicity. Clinical observations, body weight, hematology, coagulation, clinical chemistry, urinalysis, immunotoxicity, gross necropsy, and histopathology were assessed. Toxicokinetic parameters were analyzed as an indication of LF bioavailability, and anti-LF antibody assays were conducted to detect antibodies produced against LF to measure immunogenicity. No treatment related toxicologically significant changes were observed. Based on the absence of toxicologically relevant changes, effera™ is well tolerated in rats at doses up to 2000 mg rhLF/kg/day, an amount ∼400 times that of the estimated daily intake at the 90th percentile proposed for human adult use.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"125-140"},"PeriodicalIF":1.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Nonclinical Safety Assessment of a Novel Anti-CEACAM5 Antibody Exatecan Conjugate Predicts a Low Risk for Interstitial Lung Disease (ILD) in Patients-The Putative Mechanism Behind ILD. 新型抗ceacam5抗体Exatecan偶联物的非临床安全性评估预测间质性肺疾病（ILD）患者的低风险- ILD背后的推测机制

IF 1.2 4区医学

International Journal of Toxicology Pub Date : 2025-03-01 Epub Date: 2025-01-04 DOI: 10.1177/10915818241306039

Willem N Sloot, Elisa Bertotti, Manuela Onidi, Andrea Paoletti, Ilse De Salve, Patrizia Tavano, Enrico Vigna, Gundi Mueller

{"title":"The Nonclinical Safety Assessment of a Novel Anti-CEACAM5 Antibody Exatecan Conjugate Predicts a Low Risk for Interstitial Lung Disease (ILD) in Patients-The Putative Mechanism Behind ILD.","authors":"Willem N Sloot, Elisa Bertotti, Manuela Onidi, Andrea Paoletti, Ilse De Salve, Patrizia Tavano, Enrico Vigna, Gundi Mueller","doi":"10.1177/10915818241306039","DOIUrl":"10.1177/10915818241306039","url":null,"abstract":"The therapeutic window of antibody drug-conjugates (ADC) remains challenging due to safety issues such as interstitial lung disease (ILD) observed with specific deruxtecan-based ADCs. To avoid ILD, we designed M9140 by conjugating the maleimide-containing hydrophilic β-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 mg/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 mg/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 mg/kg and the maximum tolerated dose was 30 mg/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.","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"153-169"},"PeriodicalIF":1.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0