A Phase I, First in Human, Open-label Study of Escalating Doses of INA03 Administered Intravenously as Single Agent in Adult Patients With Relapse/Refractory Acute Leukemia

This Phase 1 Study is an open-label, non-randomized, dose escalation, safety, efficacy, pharmacokinetic, and pharmacodynamic evaluation study of INA03 administered as a single agent IV infusion every 2 weeks to patients ≥18 years of age with R/R AML, MLL, or ALL.
The study will be performed in 2 parts: a Dose Titration for Day 1 study (Part 1) followed by a Dose Escalation Part (Part 2) of INA03 used as monotherapy.

开始日期2020-05-29

申办/合作机构

Institut Jean Paoli & Irene Calmettes

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100 项与 INA-03 相关的临床结果

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100 项与 INA-03 相关的转化医学

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100 项与 INA-03 相关的专利（医药）

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项与 INA-03 相关的文献（医药）

2024-08-01·Molecular Cancer Therapeutics

INA03: A Potent Transferrin-Competitive Antibody–Drug Conjugate against CD71 for Safer Acute Leukemia Treatment

Article

作者: Belanger, Coralie ; Josselin, Emmanuelle ; Puissant, Alexandre ; Stubbs, Elisa ; Benajiba, Lina ; Kelly, Lois ; Koniev, Oleksandr ; Marchal, Michelle ; Merlin, Johanna ; Kolodych, Sergii ; Launay, Pierre ; Bratti, Manuela ; Collette, Yves ; Souchet, Herve ; Monteiro, Renato C. ; Pasquer, Hélène ; Castellano, Remy ; Hermine, Olivier

AbstractInnovative strategies for enhancing efficacy and overcoming drug resistance in hematologic cancers, such as using antibody–drug conjugates (ADC), have shifted the paradigm of conventional care by delivering promising outcomes in cancer therapies with a significant reduction in the risk of relapse. Transferrin receptor (TfR1), cluster of differentiation 71 (CD71), is known to be overexpressed in malignant cells and considered a potent antitumor target. Therefore, we developed an anti-CD71 ADC, INA03, a humanized antibody conjugated to monomethyl auristatin E through a 3-arylpropiolonitrile–valine–citrulline linker. In this study, we investigated the potency and safety of INA03, in competition with Transferrin (Tf), the CD71’s natural ligand, as a novel strategy to specifically target highly proliferative cells. The high expression of CD71 was confirmed on different leukemic cell lines, allowing INA03 to bind efficiently. Subsequently, INA03 rapidly internalizes into lysosomal compartments, in which its cytotoxic drug is released following cathepsin B cleavage. Downregulation of CD71 expression using shRNA highlighted that INA03-induced cell death was dependent on CD71 density at the cell surface. INA03 intravenous treatment in acute leukemia mouse models significantly reduced tumor burden, increased mouse survival, and showed no residual disease compared with conventional chemotherapies. Because INA03 competes with human Tf, a double knock-in (human CD71/human Tf) competent mouse model was generated to mimic human pharmacokinetics and pharmacodynamics. INA03 administration in human CD71/hTf mice did not reveal any improper toxicities, even at high doses. Hence, these data demonstrate the promising preclinical efficacy and safety of INA03 and support its development as a novel acute leukemia treatment.Significance: The Tf receptor is believed to be undruggable because of its ubiquitous expression. By entering into competition with its cognate ligand, the Tf and INA03 ADC can safely achieve potency.

100 项与 INA-03 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
复发性急性淋巴细胞白血病	临床1期	法国	Inatherys SAS	2020-05-29
复发性急性淋巴细胞白血病	临床1期	法国	Institut Jean Paoli & Irene Calmettes	2020-05-29
混合表型急性白血病	临床1期	法国	Institut Jean Paoli & Irene Calmettes	2020-05-29
混合表型急性白血病	临床1期	法国	Inatherys SAS	2020-05-29
难治性急性白血病	临床1期	法国	Institut Jean Paoli & Irene Calmettes	2020-05-29
难治性急性白血病	临床1期	法国	Inatherys SAS	2020-05-29
复发性急性髓细胞白血病	临床1期	法国	Institut Jean Paoli & Irene Calmettes	2020-05-29
急性淋巴细胞白血病	临床1期	-	Institut Jean Paoli & Irene Calmettes	-
急性髓性白血病	临床1期	-	Institut Jean Paoli & Irene Calmettes	-
急性双表型白血病	临床前	法国	Inatherys SAS	2020-01-22

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03957915 (ASH2023)	临床1期	急性白血病	27	INA03	鬱構構憲顧繭蓋築簾築(廠獵膚鹹願窪構衊網淵) = 鏇蓋鬱夢餘膚鬱選製餘繭壓積獵襯鹹壓糧構繭 (窪廠簾構衊壓衊壓醖膚 )	-	2023-12-11
NCT03957915 (EHA2023)	临床1期	白血病	22	INA03	繭襯願繭選壓範網憲醖(襯顧獵餘鑰憲糧餘鑰願) = 鏇鹽鏇繭簾顧襯鏇鬱範廠構醖獵觸衊鹽憲淵積 (廠齋鏇夢醖廠顧夢範夢 )	-	2023-06-08
NCT03957915 (ASCO2023) 人工标引	临床1期	白血病	22	INA03	(鑰網糧鑰蓋夢齋膚餘繭) = 範範遞襯齋膚糧簾壓淵憲繭窪餘淵鏇襯選膚鬱 (簾齋觸淵衊蓋簾鹽襯鑰 ) 更多	积极	2023-05-26