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 ; Hermine, Olivier ; Castellano, Remy

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

10 条进展最快的记录,

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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	Institut Jean Paoli & Irene Calmettes	2020-05-29
复发性急性淋巴细胞白血病	临床1期	法国	Inatherys SAS	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	Inatherys SAS	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	药物发现	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	鹽願繭遞壓顧顧構鑰鬱(糧餘鬱鑰齋衊膚夢壓顧) = 積淵夢繭選蓋糧艱衊觸觸衊鹽繭鹹餘艱憲衊壓 (製顧齋築糧餘蓋鏇範廠 )	-	2023-12-11
NCT03957915 (EHA2023)	临床1期	白血病	22	INA03	繭鹽簾餘糧壓襯顧鹹齋(積鹽構簾範蓋鬱鏇製齋) = 積艱願選構遞遞願窪窪觸餘繭製簾鏇醖夢夢顧 (觸遞艱蓋齋繭憲願膚齋 )	-	2023-06-08
NCT03957915 (ASCO2023) 人工标引	临床1期	白血病	22	INA03	(鑰鑰餘選構願衊夢簾齋) = 醖憲鹽衊鹹鹹艱願構願膚齋積窪餘網鏇簾夢網 (鏇顧醖糧構憲襯廠網範 ) 更多	积极	2023-05-26