Brain Shuttle Antibody Development Service

The blood-brain barrier (BBB) hinders the diagnosis, treatment, and development of antibody-based immunotherapies for brain diseases. Based on the latest research developments and powerful technology platform, Creative Biolabs provides clients around the world with one-stop development services for brain-shuttle antibody therapies, actively delivering molecules and antibodies of your interest across the BBB through receptor-mediated cell action.

BBB Receptors and Brain Shuttle

The BBB is a barrier to the entry of macromolecular drugs and antibodies into the brain. Under its restriction, only 0.01-0.4% of the proteins in the blood can enter the central nervous system by passive diffusion, which includes therapeutic antibodies, usually of the IgG isotype, or key enzymes that degrade Aβ in the blood, such as anti-Tau BBB shuttle antibody. Efforts to use various drugs to treat CNS disorders are increasing, but the BBB impediment makes it difficult for conventional drugs to achieve therapeutic doses in the brain.

Fig 1. Schematic drawing of the BBB model. (Lopez, 2021)

The BBB uses natural receptors expressed on brain endothelial cells for transmembrane transport. In particular, the transferrin receptor (TfR), which is widely expressed in BECs, has demonstrated the ability to transport various therapeutic molecules across the BBB. At present, many studies have proved that TfR-mediated transcytosis can realize the delivery of molecules. This allows antibody fragments that can specifically recognize and bind TFR to work as brain shuttles.

Fig 2. FcR-binding capacity of brain shuttle. (Weber, 2017)

With a powerful technical platform and professional staff, Creative Biolabs designs and develops suitable brain shuttle vectors through various approaches. By fusing a single-chain Fab fragment that can be recognized by TFR with the Fc region of the C-terminus of a traditional mAb, a multifunctional mAb that retains the natural configuration is constructed. Ideally, the Fc region binds to FcgR on the cell surface and exerts a high degree of effector function, while the BS module bind to TFR for BBB transport, and the Fab arm can be designed to carry suitable cargo for subsequent therapy.

In addition, we also fuse the active domains of specific therapeutic molecules with TFR mAbs (such as OX26) to form delivery devices that can cross the BBB and be released after crossing the membrane for therapeutic function. This immunoglobulin structure also retains the necessary effector function of the Fc region, which is involved in both antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC). Several experiments have demonstrated substantive improvements in CNS drug delivery, targeting and therapy with specially designed brain shuttle therapy.

Fig 3. Cargo delivery and BBB penetration capability of brain shuttles. (Campos, 2020)

Our Service

Creative Biolabs provides the design, processing, screening and synthesis of several BS modules or therapeutic modules for our clients all over the world, and integrate your selected modules through different approaches. In addition, we also offer a series of validation assays, including the use of surface plasmon resonance analysis and flow cytometry to detect the free binding and cell binding capacity of fusions. Aβ plaques and brain tissue sections were used to test the therapeutic modules' viability and cytotoxicity, and the BS modules' delivery ability was tested by microfluidic means or other BBB in vitro models. We also perform pharmacokinetic analysis in vitro or in vivo, providing you with intuitive, accurate and reliable experimental data. Please do not hesitate to contact us for more information.

References

1. Lopez, E.; et al. Transportation of single-domain antibodies through the blood-brain barrier. Biomolecules. 2021, 11: 1131.
2. Weber, F.; et al. Brain shuttle antibody for Alzheimer’s disease with attenuated peripheral effector function due to an inverted binding mode. Cell Reports. 2017, 22: 149-162.
3. Campos, C.R.; et al. Brain Shuttle Neprilysin reduces central Amyloid-β levels. PLoS One. 2020, 15(3): e2209850.