Abstract 580P
Background
Adaptive immunity to cancer cells forms a crucial part of cancer immunotherapy. Recently, the importance of tumour B-cell signatures were shown to correlate with melanoma survival. We investigated whether tumour-targeting antibodies could be isolated from a patient that cured (13 years tumour-free) metastatic melanoma following adoptive transfer of ex vivo expanded autologous T cells.
Methods
Patient’s peripheral blood B cells were isolated and tested for the presence of tumour-reactive B cells using AIMM’s immmortalisation technology.
Results
Antibody AT1412 was identified by virtue of its differential binding to melanoma cells as compared to healthy melanocytes. AT1412 binds the tetraspanin CD9, a broadly expressed protein involved in multiple cellular activities and cancer and induces ADCC and ADCP by macrophages. Spontaneous immune rejection of tumours was observed in HIS (human immune system) mouse models implanted with CD9 genetically-disrupted A375 melanoma (A375-CD9KO) tumour cells, while A375wt cells were not. Most notably, no tumour rejection was observed in NSG mice, indicating that blockade of CD9 on tumour cells makes them susceptible to immune rejection. CD9 has been described to negatively regulate integrin signaling. AT1412 was shown to inhibit CD9 function by enhancing adhesion and transmigration of T-cells to endothelial (HUVEC) cells. AT1412 was most potently enhancing transendothelial T-cell migration, in contrast to a high affinity version of AT1412 or ALB6 reference antibody. In immunodeficient mice harbouring a human immune system, AT1412 strongly enhanced CD8 T-cell and macrophage infiltration resulting in tumour rejection (A375 melanoma). PD-1 checkpoint blockade is further enhancing this effect. In a second melanoma model carrying a PD-1 resistant and highly aggressive tumour (SK-MEL5) AT1412 together with nivolumab was inducing full tumour rejection, while either one of the antibodies alone did not.
Conclusions
AT1412 is in preclinical development and is well tolerated up to 10 mg/kg (highest dose tested). No adverse events were observed besides a dose-dependent transient thrombocytopenia with no impact on coagulation factors or bleeding. First in Human clinical study is planned to start early 2021.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
AIMM Therapeutics.
Disclosure
R. Schotte: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. J. Villaudy: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. M. Kedde: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. K. Wagner: Shareholder/Stockholder/Stock options: AIMM Therapeutics. D. Go: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. C. Fatmawati: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. G. Moiset: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. E. Yasuda: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. M. Cercel: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. E. Frankin: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. S. van Hal-van Veen: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. P. van Helden: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. E.M.E. Verdegaal: Full/Part-time employment: Leiden University. H. van Eenennaam: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. S.H. van der Burg: Full/Part-time employment: Leiden University. H. Spits: Shareholder/Stockholder/Stock options, Full/Part-time employment: AIMM Therapeutics. All other authors have declared no conflicts of interest.