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.

Start Date29 May 2020

Sponsor / Collaborator

Institut Jean Paoli & Irene Calmettes

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100 Clinical Results associated with INA-03

100 Translational Medicine associated with INA-03

100 Patents (Medical) associated with INA-03

Literatures (Medical) associated with INA-03

01 Aug 2024·Molecular Cancer Therapeutics

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

Article

Author: 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 Deals associated with INA-03

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Acute lymphoblastic leukemia recurrent	Phase 1	FR	Inatherys SAS	29 May 2020
Acute lymphoblastic leukemia recurrent	Phase 1	FR	Institut Jean Paoli & Irene Calmettes	29 May 2020
Mixed phenotype acute leukemia	Phase 1	FR	Institut Jean Paoli & Irene Calmettes	29 May 2020
Mixed phenotype acute leukemia	Phase 1	FR	Inatherys SAS	29 May 2020
Refractory Acute Leukemia	Phase 1	FR	Institut Jean Paoli & Irene Calmettes	29 May 2020
Refractory Acute Leukemia	Phase 1	FR	Inatherys SAS	29 May 2020
Relapsing acute myeloid leukemia	Phase 1	FR	Institut Jean Paoli & Irene Calmettes	29 May 2020
Acute Lymphoblastic Leukemia	Phase 1	-	Institut Jean Paoli & Irene Calmettes	-
Acute Myeloid Leukemia	Phase 1	-	Institut Jean Paoli & Irene Calmettes	-
Acute Biphenotypic Leukemia	Preclinical	FR	Inatherys SAS	22 Jan 2020

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03957915 (ASH2023)	Phase 1	acute leukemia	27	INA03	baltmwnyjc(kpzzodlwur) = zwducwcjps uhnrrdjdkk (fthqdowcmz )	-	11 Dec 2023
NCT03957915 (EHA2023)	Phase 1	Leukemia	22	INA03	ojgpefkktf(exguinnxjo) = mrkhbnyhdz hgzafacjtw (sihnzzvbsf )	-	08 Jun 2023
NCT03957915 (ASCO2023) Manual	Phase 1	Leukemia	22	INA03	(xojzpcgfth) = dnjykiqdlp gsphcahaba (qqaqxljdkb ) View more	Positive	26 May 2023

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