In vivo biodistribution and pharmacokinetics of sotrovimab, a SARS-CoV-2 monoclonal antibody, in healthy cynomolgus monkeys.

PURPOSE: Sotrovimab (VIR-7831), a human IgG1κ monoclonal antibody (mAb), binds to a conserved epitope on the SARS-CoV-2 spike protein receptor binding domain (RBD). The Fc region of VIR-7831 contains an LS modification to promote neonatal Fc receptor (FcRn)-mediated recycling and extend its serum half-life. Here, we aimed to evaluate the impact of the LS modification on tissue biodistribution, by comparing VIR-7831 to its non-LS-modified equivalent, VIR-7831-WT, in cynomolgus monkeys. METHODS: 89Zr-based PET/CT imaging of VIR-7831 and VIR-7831-WT was performed up to 14 days post injection. All major organs were analyzed for absolute concentration as well as tissue:blood ratios, with the focus on the respiratory tract, and a physiologically based pharmacokinetics (PBPK) model was used to evaluate the tissue biodistribution kinetics. Radiomics features were also extracted from the PET images and SUV values. RESULTS: SUVmean uptake in the pulmonary bronchi for 89Zr-VIR-7831 was statistically higher than for 89Zr-VIR-7831-WT at days 6 (3.43 ± 0.55 and 2.59 ± 0.38, respectively) and 10 (2.66 ± 0.32 and 2.15 ± 0.18, respectively), while the reverse was observed in the liver at days 6 (5.14 ± 0.80 and 8.63 ± 0.89, respectively), 10 (4.52 ± 0.59 and 7.73 ± 0.66, respectively), and 14 (4.95 ± 0.65 and 7.94 ± 0.54, respectively). Though the calculated terminal half-life was 21.3 ± 3.0 days for VIR-7831 and 16.5 ± 1.1 days for VIR-7831-WT, no consistent differences were observed in the tissue:blood ratios between the antibodies except in the liver. While the lung:blood SUVmean uptake ratio for both mAbs was 0.25 on day 3, the PBPK model predicted the total lung tissue and the interstitial space to serum ratio to be 0.31 and 0.55, respectively. Radiomics analysis showed VIR-7831 had mean-centralized PET SUV distribution in the lung and liver, indicating more uniform uptake than VIR-7831-WT. CONCLUSION: The half-life extended VIR-7831 remained in circulation longer than VIR-7831-WT, consistent with enhanced FcRn binding, while the tissue:blood concentration ratios in most tissues for both drugs remained statistically indistinguishable throughout the course of the experiment. In the bronchiolar region, a higher concentration of 89Zr-VIR-7831 was detected. The data also allow unparalleled insight into tissue distribution and elimination kinetics of mAbs that can guide future biologic drug discovery efforts, while the residualizing nature of the 89Zr label sheds light on the sites of antibody catabolism.

Effects of anodyne treatment on local blood flow and cutaneous sensation of the foot in a patient with peripheral neuropathy secondary to acromegaly.

Acromegaly is an excessive amount of serum growth hormone, which may present with sensorimotor polyneuropathy, affecting sensation and/or blood flow in the limbs. Symptoms include numbness, tingling or pain with impaired sensation including kinesthesia and proprioception. We report here of a 48-year-old male with a defined diagnosis of acromegaly and surgical excision of a pituitary adenoma 20 years ago. Recently he reports feet stepping on, and not feeling, objects under foot and balance problems starting 10 years ago. This study used a single-subject A-B-A design to show that behavioral changes are evident only in the presence of an intervention. Intervention consisted of Monochromatic Infrared Light Energy (MIRE), delivered by the Anodyne Therapy System (ATS). The DRT-4 laser Doppler measured red blood cell flux (flow), concentration and velocity. Levels of significance utilized the two standard deviation band method. Peripheral sensation of eight sites on each foot assessed using Semmes-Weinstein monofilaments (SWM) revealed a lack of sensation in the feet. A treatment effect as exhibited by blood flow velocity and red blood cell concentration was detected after the third week of treatment indicating peripheral dilation of the microvasculature. MIRE was an effective intervention for the treatment of acromegaly - induced polyneuropathy in this patient.