The endothelin (ET) axis regulates multiple physiological functions and its two receptor subtypes (ETA and ETB) are therapeutic targets approved by the European (EMA) and American (FDA) health authorities for clinical trials in patients with certain cancers. SPI and BioMaps researchers have been collaborating for several years on the design and development of therapeutic antibodies or ADCs (antibody-drug conjugates) targeting these two receptor subtypes, which play a crucial role in the tumour progression of two particularly aggressive cancers, glioblastoma and melanoma.
In the studies presented here, they set out to develop new applications for their innovative antibodies, rendomab A63 (RA63) (publication 1) and rendomab B49 (RB49) (publication 2), targeting ETA and ETB respectively, in preclinical models of these two diseases.
Glioblastoma and RA63 for surgical assistance applications
Based on the observation that endothelin A receptors (ETA), which are over-expressed in glioblastoma stem cells, are an interesting target for imaging these primary brain tumours (see previous study, box), the authors assessed the efficacy of RA63, which they functionalised into [89Zr]Zr-axiRA63-MOMIP, a new preclinical bimodal imaging agent that can be detected by immunoPET and immunofluorescence. PET imaging of [89Zr]Zr-axiRA63-MOMIP clearly revealed tumour foci (ETA+ cells) in an orthotopic model of human glioblastoma, while intraoperative fluorescence imaging allowed almost complete resection of the tumour.
Melanoma and RB49 for better patient stratification
Knowing that RB49 has a strong affinity for human melanoma cells, which overexpress the ETB receptor, the authors developed a chimeric form of this antibody which they conjugated with monomethyl auristatin E, a highly potent synthetic anti-cancer agent. They showed that this new ADC, xiRB49-MMAE, drastically inhibited melanoma growth after just two injections of this biomedicine, in a preclinical model bearing an ETB+ tumour xenograft. xiRB49-MMAE also showed high binding efficiency to human metastatic melanoma lymph nodes.
By demonstrating the theranostic potential of these innovative antibodies, targeting ETA+ and/or ETB+ tumours, this work represents a significant advance towards increasingly specific personalised therapeutic strategies (tumour detection, selection of patients eligible for treatment, monitoring of disease progression).
Contacts : Didier Boquet (didier.boquet@cea.fr) and Charles Truillet (charles.truillet@universite-paris-saclay.fr)
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Theranostics (a neologism derived from the contraction of
therapeutics and
diagnostics) is based on the use of specific agents capable of identifying and treating cancer cells.
- In a
previous study, carried out in a rodent model of glioblastoma, the researchers used PET imaging to monitor the fate of a CEA-patented monoclonal antibody, Rendomab A63 (RA63), specific for the ETA receptor, and revealed the high potential of this zirconium-89-labelled antibody to detect ETA+ tumours specifically.
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[89Zr]Zr-axiRA63-MOMIP: single-molecule multimodal imaging platform (MOMIP), consisting of a fluorophore (IRDye800CW) and a positron-emitting radiometal chelator (desferroxamine B, DFO), conjugated with the axiRA63 antibody targeting ETA receptors.
- The clinical development of these theranostic antibodies is being carried out by
Skymab Biotherapeutics, an SPI spin-off (DMTS) which won a
Pfizer Golden Ticket in 2024.