Seagen (Canada)

Abstract There are four vedotin drug linker containing antibody drug conjugates currently approved for treating cancer patients, proving that this technology platform is an effective modality for the treatment of both hematologic and solid tumors. The primary mechanism of vedotin ADCs, direct cytotoxicity, is the result of intracellular release of monomethyl auristatin E (MMAE) after cleavage of the valine-citrulline (Val-Cit) dipeptide by lysosomal proteases. However, off-tumor delivery of MMAE can result in dose limiting bone marrow toxicity in preclinical models. Maintaining potency in cancer cells while reducing the bone marrow toxicity of vedotin ADCs could allow higher or more frequent clinical dosing and potentially improved response rates and patient outcomes. To decrease bone marrow toxicity of MMAE empowered ADCs, we developed a process to identify peptidic linker systems that provide selectivity for cancer cells over bone marrow cells. From this process we identified a tripeptide sequence (D-leucine-alanine-glutamate, dLAE) that is preferentially cleaved in cancer cells and used it to develop a drug linker that releases MMAE upon cleavage of this tripeptide. Here, we present in vitro and in vivo data comparing ADCs containing vedotin and dLAE tripeptide drug linkers. While ADCs with the dLAE drug linker had comparable in vitro cytotoxicity and antitumor activity to vedotin, the dLAE ADCs had a higher maximum tolerated dose in exploratory rat and cynomolgus macaque toxicity studies due to a reduction in bone marrow toxicity. Reduced bone marrow toxicity was correlated with decreased linker catabolism in bone marrow cells for conjugates bearing the dLAE tripeptide compared to Val-Cit, while similar catabolism was observed in cancer cells. Together, these preclinical data highlight that changing the peptide of the vedotin drug linker from Val-Cit to dLAE can yield ADCs with an improved preclinical therapeutic window. Given the preclinical characteristics of the dLAE drug linker, a clinical trial is being planned to evaluate an anti-CD30 ADC (SGN-35T). Citation Format: Noah A Bindman, Roma Yumul, Erica E McKinney, Scott Blackburn, Nicole Blesie, Xinqun Zhang, Brendan Drouhard, Sarah Anderson, Calvin Neace, David Ortiz, KC Crowder, Nancy Everds, Chris Carosino, Forgivemore Magunda, Django Sussman, Esther Trueblood, Nicole M. Okeley, Peter Senter. Discovery of a novel auristatin antibody drug conjugate drug linker with equal efficacy and reduced bone marrow toxicity compared to vedotin [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C113.

Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) imposes several conditions on pathology institutes that develop and use in-house in vitro diagnostic medical devices (IH-IVDs). However, not all of these conditions need to be implemented immediately after the IVDR entered into force on 26May 2022. Based on an amending regulation of the European Parliament and the Council of the European Union, the requirements for IH-IVDs will be phased in. Conformity with the essential safety and performance requirements of annexI must be ensured from May2022. With this article, we would like to present the practical implementation of the currently valid conditions for IH-IVDs at the Institute of Pathology at the University Hospital of Heidelberg, in order to provide possible assistance to other institutions. In addition to the intensive work on the requirements for IH-IVDs, several guidance documents and handouts provide orientation for the implementation and harmonisation of the requirements for healthcare institutions mentioned in Article5(5). Exchange in academic network structures is also of great importance for the interpretation and practical implementation of the IVDR. For university and nonuniversity institutions, ensuring conformity with the IVDR represents afurther challenge in terms of personnel and time, in addition to the essential tasks of patient care, teaching and research and the further development of methods for optimal and targeted diagnostics, as well as the maintenance of the constantly evolving quality management system.

Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.

Survivors of childhood acute lymphoblastic leukemia (ALL) exhibit increased rates of neurocognitive deficits. This study was conducted to test whether interpatient variability in neurocognitive outcomes can be explained by polymorphisms in candidate genes conferring susceptibility to neurocognitive decline. Neurocognitive testing was conducted in 350 pediatric leukemia survivors, treated on Dana-Farber Cancer Institute ALL Consortium Protocols 95-01 or 00-01. Genomic DNA was isolated from bone marrow collected at remission. Candidate polymorphisms were selected on the basis of prior literature, targeting genes related to drug metabolism, oxidative damage, altered neurotransmission, neuroinflammation, and folate physiology. Single nucleotide polymorphisms were detected using either a customized multiplexed Sequenom MassARRAY assay or polymerase chain reaction-based allelic discrimination assays. Multivariable logistic regression models were used to estimate the effects of genotype on neurocognitive outcomes, adjusted for the effects of demographic and treatment variables. False-discovery rate correction was made for multiple hypothesis testing, indicated as a Q value. Inferior cognitive or behavioral outcomes were associated with polymorphisms in three genes related to oxidative stress and/or neuroinflammation: NOS3 (IQ, Q = 0.008; Vocabulary Q = 0.011; Matrix Reasoning Q = 0.008), SLCO2A1 (IQ Q = 0.043; Digit Span Q = 0.006; Block Design Q = 0.076), and COMT (Behavioral Assessment System for Children-2 Attention Q = 0.080; and Hyperactivity Q = 0.084). Survivors homozygous for NOS3 894T, with at least one SLCO2A1 variant G allele or with at least one GSTP1 variant allele, had lower mean estimated IQ scores than those without these genotypes. These data are consistent with the hypothesis that oxidative damage contributes to chemotherapy-associated neurocognitive decline among children with leukemia.

The purpose of this study was to develop a biodegradable triblock copolymer, mPEG-PLGA-mPEG-based delivery system for long-term controlled release of salmon calcitonin (sCT) after single subcutaneous injection. The delivery system was prepared by dissolving sCT into polymer solution. In vitro release of sCT from the delivery systems was studied in phosphate buffer saline (PBS, pH 7.4) at 37 degrees C. Stability of released sCT and sCT remaining in gel formulation was evaluated using circular dichroism, HPLC and MALDI-TOF mass spectrometry. In vivo absorption and therapeutic efficacy of sCT from the polymeric formulations were examined in female wistar rats and methylprednisolone acetate (MPA)-induced osteoporosis rat model, respectively. The polymeric formulations of sCT showed long term controlled release (~20 to 40 days) of sCT in its conformationally and chemically stable form. The sCT polymeric formulations controlled the release of sCT over ~20 to 40 days and prevented MPA induced osteoporosis in vivo. The released sCT was biologically active in terms of lowering serum calcium level. The triblock copolymer delivery systems controlled the release of sCT in vitro and in vivo in chemically and conformationally stable as well as biologically active and therapeutically effective form.

Expression of CD70, a member of the tumor necrosis factor superfamily, is restricted to activated T-and B-lymphocytes and mature dendritic cells. Binding of CD70 to its receptor, CD27, is important in priming, effector functions, differentiation and memory formation of T-cells as well as plasma and memory B-cell generation. Antibody blockade of CD70-CD27 interaction inhibits the onset of experimental autoimmune encephalomyelits and cardiac allograft rejection in mice. CD70 has been also detected on hematological tumors and on carcinomas. The highly restricted expression pattern of CD70 in normal tissues and its widespread expression in various malignancies as well as its potential role in autoimmune and inflammatory conditions makes it an attractive target for antibody-based therapeutics. This chapter provides an overview of the physiological role of CD70-CD27 interactions and discusses various approaches to target this pathway for therapeutic use in cancers and autoimmunity.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTPeter D. Senter and Jindřich KopečekView Author Information Seattle Genetics, 21823 30th Drive SE, Bothell, Washington 98021 E-mail: [email protected] Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 S 2000 E, Room 201, Salt Lake City, Utah 84112 E-mail: [email protected]Cite this: Molecular Pharmaceutics 2004, 1, 6, 395–398Publication Date (Web):November 8, 2004Publication History Published online8 November 2004Published inissue 1 November 2004https://pubs.acs.org/doi/10.1021/mp040010xhttps://doi.org/10.1021/mp040010xeditorialACS PublicationsCopyright © 2004 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views649Altmetric-Citations11LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (27 KB) Get e-Alertsclose Get e-Alerts