Abstract 11P
Background
Iron uptake plays a critical role in numerous biological processes, including cellular growth, and proliferation. Intracellular iron delivery occurs via the endocytosis of the transferrin receptor, TfR1 (CD71). As a developmentally essential protein, CD71 is ubiquitously expressed at low levels in normal cells (except erythroblasts) but is highly expressed in proliferating cancer cells. This overexpression, combined with CD71’s high internalization efficiency in tumors, makes our product INA03 an ideal candidate for an ADC program.
Methods
A novel valine-citrulline linker conjugated to an antimitotic payload (MMAE) was used to couple a humanized IgG4 anti-human CD71 antibody. In vitro activity was evaluated across several cancer cell lines as well as in activated and resting T lymphocytes. In vivo efficacy was assessed in multiple xenograft mouse models of triple-negative breast cancer (TNBC). Toxicity and comparisons with other anti-CD71 ADCs were investigated using human CD71 / human transferrin double knock-in mice.
Results
INA03 demonstrated rapid endocytosis, delivering its payload efficiently to lysosomal compartments, enabling release of the attached MMAE in targeted cells. INA03 induced potent cell death across all breast cancer cell lines tested. Significant reductions in tumor growth were observed in several animal models, including patient-derived xenograft models, correlating with tumoral CD71 expression. Immunohistochemistry revealed higher CD71 expression in triple-negative breast cancers compared to other breast cancer subtypes. Furthermore, repeated dosing effectively controlled tumor relapse. By competing with transferrin, the natural ligand of CD71, INA03 selectively induced apoptosis in highly proliferative cells. This specificity was not observed with other anti-CD71 ADCs, contributing to INA03 superior safety profile.
Conclusions
A clinical trial evaluating INA03 ADC in patients with refractory/relapsed acute myeloid leukemia (NCT03957915) is ongoing, with the recommended phase 2 dose under investigation for hematologic malignancies. But given its potent activity in TNBC preclinical models, INA03 is intended for future development also in solid tumors.
Clinical trial identification
NCT03957915.
Editorial acknowledgement
Legal entity responsible for the study
Inatherys.
Funding
Inatherys.
Disclosure
P. Launay: Financial Interests, Personal, Member: Inatherys.