Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Abstract

Transferrin receptor 1 (TfR1) mediated transcytosis is an attractive strategy to enhance brain uptake of protein drugs, but translation remains a challenge. Here, a single domain shark antibody VNAR fragment (TXB2) with similar affinity to murine and human TfR1 was used to shuttle protein cargo into the brain. TXB2 was fused to a human IgG1 Fc domain (hFc) or to the amyloid‐β (Aβ) antibody bapineuzumab (Bapi). TXB2‐hFc displayed 20‐fold higher brain concentrations compared with a control VNAR‐hFc at 18 hours post‐injection in wt mice. At the same time point, brain concentrations of Bapi‐TXB2 was threefold higher than Bapi. In transgenic mice overexpressing human Aβ, the brain‐to‐blood concentration ratio increased with time due to interaction with intracerebral Aβ deposits. The relatively stable threefold difference between Bapi‐TXB2 and Bapi was observed for up to 6 days after injection. PET imaging and ex vivo autoradiography revealed more parenchymal distribution of Bapi‐TXB2 compared with Bapi. In conclusion, the TXB2 VNAR shuttle markedly increased brain uptake of protein cargo and increased brain concentrations of the Aβ binding antibody Bapi.

Brain pharmacokinetics of two BBB penetrating bispecific antibodies of different size

“…On the other hand, deiodination and degradation would also be interpreted as removal of the antibody, and as discussed previously, elimination rate was similar for both antibodies. We have previously shown that iodine-125 radiolabelling is stable with very low levels of free iodine-125 in brain samples after antibody injection [ 8 ]. Still, it should be kept in mind that antibody and iodine-125 to some extent could be separate entities.…”

11C-PiB and124I-Antibody PET Provide Differing Estimates of Brain Amyloid-β After Therapeutic Intervention

“…PET ligands such as 11 C-Pittsburgh compound B ( 11 C-PiB) and several later developed analogues bind to fibrillar Aβ, i.e. the form of Aβ found in insoluble amyloid plaques.…”

“…However, Aβ aggregation starts years before any clinical symptoms emerge, and it appears as the PET signal with amyloid radioligands such as 11 C-PiB become saturated rather early during disease progression (2,3). In contrast, nonfibrillar Aβ oligomers and protofibrils have been reported to display a more dynamic profile during the course of the clinical stages of the disease and may therefore be better biomarkers for disease severity than amyloid plaques (3,4).…”

“…A potential strategy to image nonfibrillar Aβ aggregates, rather than plaques, and thus a way to circumvent the limitations of 11 C-PiB and other amyloid radioligands could be to use an antibody-based PET approach. Antibodies are characterized by high and specific binding to their target, and can be generated to show selective affinity for a specific aggregation form of Aβ, e.g.…”

“…The aim of this study was to compare the ability of the clinically established radioligand 11 C-PiB and the novel protofibril selective radioligand 124 I-RmAb158-scFv158 to detect and quantify effects of anti-Aβ intervention using BACE-1 inhibitor NB-360 as a model drug. The study was performed in two different models: 1) the ArcSwe mouse model that shows 11 C-PiB positivity between the age of 12 and 18 months (9,20) and 2) in the App NL-G-F knock-in mouse model harboring the Arctic, Swedish and Iberian (APP I716F) mutations that is characterized by diffuse Aβ pathology that is not readily detected by amyloid imaging with PET (21). By inclusion of old mice, characterized by abundant brain Aβ pathology, the study was designed to resemble the disease stage when patients are likely to be diagnosed and potentially enrolled into clinical trials of novel drug candidates.…”