BBBporter™ Technology Platform — RMT-Based Brain Drug Delivery

The blood-brain barrier (BBB) plays a critical role in maintaining the proper functioning of the brain by preventing the entry of most biomolecules. However, the BBB also restricts access to large-molecule therapeutics designed to treat central nervous system (CNS) disorders. A promising approach for overcoming this problem to deliver drugs is receptor mediated transport (RMT) system, which employs vesicular trafficking to carry ligands across the endothelial cells of the BBB.

Based on the BBBporter™ technology platform, our team of experts can support the development of efficient drug delivery to the brain through specific RMT receptors, such as the transferrin receptor (TfR) and CD98 heavy chain (CD98hc). Ace Therapeutics offers end-to-end contract research services, from RMT target discovery to preclinical validation of RMT-targeting biologics, to accelerate your CNS targeting programs.

High Brain Delivery Brain Specific Optimal Binding

antibodydrug conjugation modality impacts overall therapeutic

Industry Pain Points in Brain Drug Delivery

Despite the breakthroughs of biologics in treating CNS disorders, brain-targeted drug delivery remains severely hindered by the BBB. The main challenges include:

Low brain penetration efficiency: The BBB restricts over 98% of therapeutic molecules, including most small molecules and virtually all biologics, from entering the brain.
Reduced CNS exposure due to efflux transporters: The BBB contains active influx and efflux transporters that can pump drugs out of the brain, reducing their concentration at the intended target site.
BBB as a potential barrier to drug metabolism: The role of the BBB in interfering with drug metabolism and activity remains underexplored but may further compromise therapeutic outcomes.
Limited efficacy of current drug delivery methods: Many emerging delivery systems, such as viral vectors, nanoparticles, and lipid-based carriers, may induce toxicity, immune responses, or compatibility issues, which limit their application.
Low predictability and high failure rates: Current delivery strategies often lack predictability, contributing to high failure rates in CNS drug development and escalating development costs.

We provide RMT-based brain drug delivery services to overcome these bottlenecks.

Scientific Principles Behind RMT-Mediated BBB Transpor

RMT is a key physiological mechanism that enables substances to cross the BBB selectively through receptor-ligand interactions. This process involves ligand binding to receptors on brain endothelial cells, followed by intracellular trafficking and release into the brain. The RMT process involves four key steps:

The process begins when a protein ligand or an RMT-targeting therapeutic binds to a specific receptor located on the apical plasma membrane.
This triggers membrane invagination and the formation of an intracellular vesicle via endocytosis. Once internalized, the receptor-ligand complex within the vesicle can be directed to multiple intracellular pathways.
In some cases, the vesicle is recycled back to the apical plasma membrane.
Alternatively, it may be transported to the basolateral plasma membrane, where fusion with the membrane releases its contents into the brain parenchyma—a process known as transcytosis.
Another possible fate is delivery to lysosomes for degradation of vesicular contents.
An RMT-targeting antibody binding to and trafficking with a transmembrane receptor is shown as an example of the mechanism by which RMT-targeting vectors gain access to the brain.

Fig. 1 Schematic of the BBB RMT mechanism. (Lajoie, *et al.*, 2015)

Efficient Brain Delivery of Biologics via BBBporter™ Technology Platform

RMT has emerged as a promising strategy for the delivery of biologics to the brain. Ace Therapeutics is committed to facilitating the transport of biologics across the BBB into the brain via the RMT based on the BBBporter™ technology platform. Once a targeting vector and its conjugated drug cargo bind to receptors on the blood side of the brain endothelium, the vector-payload complex undergoes rapid internalization and subsequent intra/transcellular trafficking. This ultimately leads to payload delivery into cells and across the BBB into the brain via transport and transcytosis processes respectively.

Our Customized RMT-Targeting Therapeutics Development Services

Ace Therapeutics provides a comprehensive and modular preclinical contract research service that cover the entire process of developing RMT-targeting therapeutics.

BBB RMT Target Identification and Screening Services

Our approach integrates molecular profiling or "omics" analyses with phenotypic screening approaches to help clients identify RMT receptors and screen RMT-targeting ligands. We support the discovery of novel RMT targets, accelerating the development of drugs that can penetrate the brain for the treatment of neurological diseases.

RMT receptor identification and validation
RMT-targeting antibody or peptide screening

RMT-Targeting Vector Optimization and Validation Services

Our extensive in silico/computational analyses and mechanism-based peptide optimization allows us to help clients generate RMT-targeting antibody or peptide variants with a broad range of biological properties. We can also validate their intracellular trafficking and BBB transcytosis in vitro and in vivo.

RMT-targeting antibody optimization
RMT-targeting peptide optimization
RMT-targeting vector validation

RMT-Targeting Biologics Development Services

Ace Therapeutics provides RMT-targeting biologics development services to help clients design BBB delivery vector-drug conjugates for optimal brain-targeted drug delivery. Our expertise spans antibody engineering, conjugate optimization, nanoparticle formulation, and preclinical validation to accelerate the development of RMT-based drug delivery systems.

Couple the biologic to the RMT targeting moiety using direct conjugation methods
Design the formulation of nanoparticles decorated with RMT targeting ligands, and loaded with the biologics of interest

In Vitro Evaluation of RMT-Targeting Biologics

Our in vitro evaluation platform offers a suite of scientifically validated assays designed to assess the BBB transcytosis potential, intracellular trafficking efficiency within the endosomal compartment, and functional efficacy of RMT-targeting biologics. Our rigorous in vitro testing yields critical insights into the transcytosis efficiency and therapeutic potential of RMT-targeting biologics.

In vitro BBB models, e.g., brain capillary endothelial cells (BCECs), human induced pluripotent stem cell (iPSC)-derived BBB models.
In vitro assays, e.g., RMT receptor binding assays, in vitro transcytosis assays.

In Vivo Evaluation of RMT-Targeting Biologics

Ace Therapeutics is committed to advancing the preclinical development of RMT-targeting biologics through in vivo evaluation services. Our in vivo evaluation platform is designed to help clients assess the pharmacokinetics, brain biodistribution, and therapeutic efficacy of their RMT-targeting biologics.

Biodistribution and pharmacokinetics (PK) studies
Efficacy studies in animal models

Therapeutic Areas

Our BBBporter™ technology platform supports drug development for a wide range of CNS disorders, including:

Neurodegenerative Diseases

Parkinson's Disease (PD)
Alzheimer's Disease (AD)
Multiple Sclerosis (MS)
Huntington's disease (HD)

Neurovascular Diseases

Stroke
Transient Ischemic Attack (TIA)

Other CNS Diseases

Lysosomal storage disease
Brain or spinal cord injury
Epilepsy

Our Key Advantages

We provide a comprehensive, science-driven solution to overcome the challenges of brain drug delivery, empowering your CNS programs from discovery to development.

Professional and Experienced Team

Our experienced team has deep expertise in BBB biology, RMT mechanisms, and brain drug delivery strategies.

Cross-Species Receptor Targeting

We can develop RMT-targeting vectors that can bind to both non-human and human forms of the target receptor, and optimize them to generate variants with unique properties.

End-to-End Integration Capabilities

From RMT target discovery, vector engineering, to preclinical validation, we offer full-service support to accelerate the development of RMT-targeted biologics.

Rapid Turnaround and Collaborative Support

We offer dedicated project managers, transparent timelines, and collaborative consultation to help you meet your program goals efficiently.

Frequently Asked Questions (FAQs)

If you have additional questions or need a customized solution, we welcome you to contact our team. We're here to support your CNS drug delivery journey.

What types of therapeutics are compatible with the BBBporter™ technology platform?

Our RMT-targeting therapeutics development services are applicable to a wide range of biologics and therapeutic modalities, including:

Therapeutic monoclonal antibodies
Protein and enzyme therapeutics
Gene therapies
Lipid nanoParticles (LNPs)

We tailor the RMT-based brain drug delivery strategy based on the client's molecule, target, and therapeutic areas.

Can we evaluate BBB delivery efficiency across different animal models?

Yes. We offer cross-species in vivo validation, including pharmacodynamics (PD), pharmacokinetics (PK), biodistribution, and brain penetration studies in mice, rats, rabbits, and non-human primates. This allows us to provide translational data to support preclinical decision-making.

At what stages of drug development can BBBporter™ technology platform be applied?

We provide support at multiple stages of drug development:

Early discovery stage: RMT target screening and vector optimization.
Preclinical development stage: RMT-targeting biologics design and preclinical candidate drug evaluation.

We provide modular and flexible services, enabling clients to choose full or partial workflows depending on their needs.

Can you optimize BBB delivery for an existing therapeutic candidate?

Absolutely. We offer BBB delivery optimization services for existing molecules, including RMT vector fusion design, binding affinity tuning, transcytosis efficiency testing, and immunogenicity assessments to improve CNS exposure.

What is the typical collaboration process with our team?

Our standard workflow includes:

Initial consultation and project goal alignment
Proposal design and timeline planning
Contract signing and project initiation
Milestone-based data delivery and progress updates
Final reporting and post-project support

Reference

Lajoie, J. M., & Shusta, E. V. (2015). Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier. Annual review of pharmacology and toxicology, 55(1), 613-631.

RMT-Based Brain Drug Delivery Services