TfR1 & CD98 Fully Human BBB Shuttle Antibodies for CNS Diseases

Roche recently partnered with Manifold Bio in a deal worth up to $2 billion to develop next-generation blood–brain-barrier (BBB) shuttles for neurological therapies, underscoring pharma’s growing focus on CNS delivery.

The BBB protects the brain but blocks most drugs, limiting treatments for CNS diseases such as Alzheimer’s, Parkinson’s, and brain tumors. Receptor-mediated transcytosis (RMT) enables targeted delivery of large molecules across the BBB. JR-141, a TfR1-mediated antibody–enzyme fusion approved in Japan for Hunter syndrome, is the first antibody-based BBB shuttle therapeutic. While TfR1 (CD71) is a key transporter, its peripheral expression and clearance pose challenges, whereas CD98hc is emerging as a promising alternative offering sustained brain delivery with lower systemic risk.

Transport Mechanisms at the BBB and Ligand-Mediated Drug Delivery

(Li, Liu, and Zhao 2025)

RenMice^® Platform for Receptor-Mediated BBB Shuttle Discovery

Leveraging its RenMice^® fully human antibody discovery platforms, Biocytogen is developing receptor-mediated BBB shuttles targeting TfR1 (CD71) and CD98, providing innovative solutions for brain-targeted biologics and drug delivery.

Key Advantages:

• Clinically Validated / High-Potential Therapeutic Targets: TfR1 (validated) and CD98 (high potential) have been demonstrated to mediate antibody transport across the BBB.
• Powerful Discovery Engine: Biocytogen's advanced RenMab^®, RenLite^®, RenNano^® platforms support the development of diverse, fully human antibodies with excellent developability profiles.

Data Highlights:

RenNano^® Anti-TfR1 Antibody

The fully human RenNano^® heavy-chain-only anti-TfR1 antibody (Ab26) :

• Conjugation: Achieved homogeneous, site-specific DAR1 conjugation (e.g., vcMMAE)
• Binding: Preserved native binding affinity to TfR1
• Function: Maintained BBB transport capability
• Stability: Retained overall biophysical stability after conjugation

▷ Monovalent Ab26 Outperforms Bivalent Form in Brain Uptake

▷ Efficient Conjugation of DAR 1 Payload (vcMMAE) to Ab26

Anti-CD98hc Antibody

CD98hc, a component of amino acid transporters, is emerging as a promising target for BBB shuttle development. Multiple RenNano^® and RenLite^® anti-CD98 clones developed by Biocytogen have demonstrated improved BBB penetration compared with benchmark antibodies. Contact us to request the full data package!

The approval of the TfR1-targeted antibody JR-141 validates the clinical potential of BBB-penetrating therapies, reinforcing the growing demand for effective CNS delivery solutions. With 1M+ fully human antibody sequences, 4,390+ validated models, and active collaborations with the top 10 global pharma companies, Biocytogen is accelerating the development of next-generation antibody therapeutics, including those targeting complex CNS diseases.

Contact us to explore collaboration opportunities in BBB shuttle discovery and CNS drug development!

Frequently Asked Questions (FAQs)

1. What are BBB shuttles and why do they matter?

BBB shuttles are engineered biologics—often antibodies fused to a BBB-transport module—that bind endothelial receptors and use receptor-mediated transcytosis (RMT) to deliver therapies across the blood–brain barrier, overcoming the fact that the BBB blocks most large-molecule drugs from reaching the brain. This approach holds promise for treating CNS diseases such as Alzheimer’s, Parkinson’s, and brain tumors.

2. How does Biocytogen’s RenMice^® platform advance BBB shuttle discovery?

Biocytogen’s RenMice^® platforms (RenMab^®, RenLite^®, RenNano^®) support the development of fully human monoclonal, bispecific, and VHH antibodies targeting TfR1 (CD71) and CD98hc, accelerating the discovery of safe and effective CNS-targeted therapeutics.

3. What makes TfR1 and CD98hc key BBB shuttle targets?

TfR1 is a validated BBB transporter used in JR-141, the first approved antibody-based shuttle for Hunter syndrome. CD98hc, a newer target, offers sustained brain delivery with lower systemic risk, making it promising for next-gen therapies.

4. What progress has Biocytogen made in BBB shuttle design?

Biocytogen’s fully human heavy-chain-only anti-TfR1 antibody achieved site-specific DAR1 conjugation (vcMMAE) while preserving BBB transport and binding. New RenNano^® and RenLite^® anti-CD98hc clones also show superior brain penetration over benchmarks.

Reference:

Li, Yuanke, Ruiying Liu, and Zhen Zhao. "Targeting brain drug delivery with macromolecules through receptor-mediated transcytosis." Pharmaceutics 17.1 (2025): 109.