A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Targeting CD33+ acute myeloid leukemia with GLK-33, a lintuzumab-auristatin conjugate with a wide therapeutic window
Tekijät: Satomaa, Tero; Pynnönen, Henna; Aitio, Olli; Hiltunen, Jukka O.; Pitkänen, Virve; Lähteenmäki, Tuula; Kotiranta, Titta; Heiskanen, Annamari; Hänninen, Anna-Liisa; Niemelä, Ritva; Helin, Jari; Kuusanmäki, Heikki; Vänttinen, Ida; Rathod, Ramji; Nieminen, Anni I.; Yatkin, Emrah; Heckman, Caroline A.; Kontro, Mika; Saarinen, Juhani
Kustantaja: American Association for Cancer Research
Julkaisuvuosi: 2024
Lehti: Molecular Cancer Therapeutics
Tietokannassa oleva lehden nimi: Molecular cancer therapeutics
Lehden akronyymi: Mol Cancer Ther
Vuosikerta: 23
Numero: 8
Aloitussivu: 1073
Lopetussivu: 1083
ISSN: 1535-7163
eISSN: 1538-8514
DOI: https://doi.org/10.1158/1535-7163.MCT-23-0720
Julkaisun avoimuus kirjaamishetkellä: Ei avoimesti saatavilla
Julkaisukanavan avoimuus : Osittain avoin julkaisukanava
Verkko-osoite: https://aacrjournals.org/mct/article/doi/10.1158/1535-7163.MCT-23-0720/742107
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/387605047
Rinnakkaistallenteen lisenssi: muu lisenssi
Rinnakkaistallennetun julkaisun versio: Final draft
CD33 (Siglec-3) is a cell surface receptor expressed in approximately 90% of AML blasts, making it an attractive target for therapy of acute myeloid leukemia (AML). While previous CD33-targeting antibody-drug conjugates (ADCs) like gemtuzumab ozogamicin (GO, Mylotarg) have shown efficacy in AML treatment, they have suffered from toxicity and narrow therapeutic window. This study aimed to develop a novel ADC with improved tolerability and a wider therapeutic window. GLK-33 consists of the anti-CD33 antibody lintuzumab and eight mavg-MMAU auristatin linker-payloads per antibody. The experimental methods included testing in cell cultures, patient-derived samples, mouse xenograft models, and rat toxicology studies. GLK-33 exhibited remarkable efficacy in reducing cell viability within CD33-positive leukemia cell lines and primary AML samples. Notably, GLK-33 demonstrated anti-tumor activity at single dose as low as 300 µg/kg in mice, while maintaining tolerability at single dose of 20 - 30 mg/kg in rats. In contrast to both GO and lintuzumab vedotin, GLK-33 exhibited a wide therapeutic window and activity against multidrug-resistant cells. The development of GLK-33 addresses the limitations of previous ADCs, offering a wider therapeutic window, improved tolerability, and activity against drug-resistant leukemia cells. These findings encourage further exploration of GLK-33 in AML through clinical trials.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
