In-human assessment of target engagement and blockade of radiolabeled BI 765063, an anti-SIRPα antibody

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The signal regulatory protein alpha (SIRPα) receptor on myeloid cells binds cluster of differentiation (CD) antigen CD47 on tumor cells, resulting in a “don’t eat me” signal that inhibits phagocytosis. BI 765063, an anti-SIRPα antibody, may restore anti-tumor immunity by blocking this interaction. This phase I study aimed to assess target engagement and blockade of BI 765063 using quantitative 89Zr-immuno-PET, incorporating a previously developed correction method for non-target-mediated antibody catabolism. For this, four patients with advanced cancer received two cycles of [89Zr]Zr-BI 765063 and underwent three PET-scans per cycle up to 120 h post injection. The first cycle included a low dose of BI 765063 and the second a dose more than 20 times higher, intended to block the target. Directly after BI 765063 administration at the second cycle, ezabenlimab was administered to start the investigational treatment of the patients (BI 765063 + ezabenlimab, both every 3 weeks). Tumor uptake was corrected for antibody catabolism using literature-based reference values and normalized to plasma activity to calculate corrected tissue-to-plasma ratios (cTPR). Patlak analysis with the cTPR values yielded corrected net irreversible uptake rates (cKi). PET data were compared with RNA-sequencing data and macrophage marker immunohistochemistry. All ten tumor lesions showed target engagement by cTPR values at 120 h exceeding reference values. Positive cKi values were observed in all but one lesion, in which no Patlak analysis could be performed. cTPR values were lower for the blocking dose than the low dose, with five out of ten lesions within the range of non-target-mediated uptake, indicating partial target blockade. Target engagement observed by PET was supported by positive SIRPα mRNA expression and myeloid cell presence. Target engagement and blockade of BI 765063 were observed across all tumors, highlighting the potential of non-target-mediated antibody catabolism correction through cTPRs to improve quantification of target specific uptake with immuno-PET. ClinicalTrials.gov ID NCT05068102, Registered at 23 September 2021, https//clinicaltrials.gov/study/NCT05068102?term=NCT05068102.&rank=1. Question: Does the anti-SIRPα antibody BI 765063 exhibit target-mediated uptake using quantitative ⁸⁹Zr-immuno-PET with correction for antibody catabolism? Pertinent findings: In this clinical PET study, patients with solid tumors underwent multiple PET scans after both a low antibody dose and a more than 20 times higher blocking dose of [⁸⁹Zr]Zr-BI 765063. Tissue to plasma ratios support target engagement across all evaluated tumor lesions, as well as target blockade following the blocking dose administration of BI 765063. Implications for patient care: Evidence of target engagement and blockade supports the clinical potential of anti-SIRPα antibodies to restore myeloid cell phagocytic function and downstream adaptive immunity, thereby informing dose optimization and potentially improving patient outcomes.

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