遺伝性筋疾患における抗体の役割

Inherited muscular disorders such as Duchenne Muscular Dystrophy (DMD) and Myotonic Dystrophy Type 1 (DM1) are progressive genetic diseases for which curative treatments remain elusive. Recent advances in biotechnology have brought antibody-based therapies into focus as precision tools to enhance drug delivery, modulate inflammation, and extend functional benefits. This article explores the mechanisms by which antibodies contribute to current and emerging therapeutic strategies for these disorders.

Introduction

Inherited muscular disorders encompass a heterogeneous group of genetic conditions characterized by progressive skeletal muscle degeneration. Common subtypes include Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy, Myotonic Dystrophy Type 1 (DM1), and congenital muscular dystrophies. While these diseases differ in onset, severity, and genetic mutations, they share challenges in drug delivery, tissue targeting, and immune tolerance. Antibodies have emerged as key molecular tools in overcoming these obstacles.

Antibody-Oligonucleotide Conjugates (AOCs): Enhancing Delivery and Specificity

Antibody-oligonucleotide conjugates are engineered molecules that fuse antisense oligonucleotides (ASOs) with antibodies targeting muscle-specific receptors, most notably transferrin receptor 1 (TfR1). This strategy enables:

• Improved cellular uptake in skeletal, cardiac, and smooth muscle tissues

• Enhanced endosomal escape, allowing therapeutic oligonucleotides to reach their nuclear targets

• Tissue-specific biodistribution, minimizing off-target effects

Two leading examples:

1. DYNE-101 (Dyne Therapeutics): targets DMPK RNA in DM1, showing reduction in toxic RNA foci and functional improvement in early-phase trials.

2. del-zota and AOC 1001 (Avidity Biosciences): applied in DMD and DM1 respectively, with del-zota demonstrating up to 25% dystrophin restoration and significant reduction in muscle damage biomarkers.

Monoclonal Antibodies: Modulating Inflammation and Immune Barriers

In the context of muscular dystrophies, chronic inflammation accelerates muscle degradation. Monoclonal antibodies (mAbs) are being investigated for their ability to:

1. Neutralize pro-inflammatory cytokines (e.g., TNF-α, IL-6)

2. Target immune checkpoints or complement pathways contributing to muscle damage

3. Overcome immune exclusion barriers in gene therapy (e.g., antibodies against AAV capsids in DMD gene therapy candidates)

Additionally, immunomodulatory agents like imlifidase are under investigation to remove pre-existing antibodies to AAV vectors, potentially allowing redosing of gene therapies like Sarepta’s Elevidys.

Antibody-Based Cell Therapies: Targeting Cardiac Involvement in DMD

Capricor Therapeutics’ deramiocel, an allogeneic cardiosphere-derived cell therapy, leverages the regenerative and immunomodulatory effects of donor heart cells. These cells exert:

• Anti-fibrotic and anti-inflammatory actions

• Potential antibody-mediated regeneration via paracrine signaling

• Preservation of cardiac function, a critical determinant of survival in non-ambulatory DMD patients

In trials, deramiocel slowed upper limb and cardiac function decline by nearly 50%, supporting its potential as the first FDA-approved therapy for DMD-related cardiomyopathy.

Challenges and Future Directions

While antibody-based approaches offer promising solutions, key challenges remain:

• Immunogenicity of repeated dosing

• Manufacturing complexity of large conjugates and biologics

• Variable receptor expression across disease stages and patient populations

Nonetheless, the intersection of antibody engineering, genetic therapy, and muscle biology continues to evolve. With multiple antibody-driven platforms advancing to Phase III trials and anticipated regulatory submissions by 2026, the next few years may mark a paradigm shift in treating inherited muscular disorders.

Antibodies have moved beyond their traditional role in immune defense to become precision therapeutic delivery vehicles and modulators of disease pathology in inherited muscular disorders. Through innovations like AOCs, immunotherapy adjuncts, and regenerative cell therapies, antibodies are reshaping the landscape of neuromuscular disease treatment, thus offering hope for more effective, personalized interventions.