Antibody-Oligonucleotide Conjugate (AOC) Development Services

Antibody-oligonucleotide conjugates (AOCs) are a novel class of synthetic chimeric biomolecules that has been continually gaining traction in different fields of modern biotechnology. Creative Biolabs focuses on developing this new class of oligonucleotide conjugates to overcome the current limitations of oligonucleotide (ON) therapies for a wide range of serious diseases. Base on our perfect AOC platform, AOCs can be designed, engineered, and developed to combine the tissue and disease selectivity of monoclonal antibodies (mAbs) and the precision of oligonucleotide-based therapies to access previously undruggable tissue and cell types, and more effectively target underlying genetic drivers of diseases. Creative Biolabs provides comprehensive AOC development services for our honor clients and the AOCs candidates derived from our platform will have the potential to offer distinct advantages over ON itself.

Background

AOC Introduction

Combining different functionalities in one entity by generating chimeric constructs has always been an attractive strategy in various fields such as biology, chemistry, and medicine. Two important families of biomolecules have gained a lot of attention and have already revolutionized the field of diagnostics and therapeutics, they are mAbs and Oligonucleotide Synthesis (ONs). Combining the distinct functionalities of mAb and ON in one chimeric construct (namely AOC) has been explored. The AOC constructs can trigger complex biological mechanisms ranging from immune responses to cell differentiation, apoptosis, and protein expression, thus AOC attracted a lot of interest in both academic and industrial fields.

Conjugation Strategies of AOC Development

Similar to antibody-drug conjugation, ONs can be attached to different sites of an antibody using diverse conjugation chemistry. Multiple endogenous amino acids can serve as potential conjugation sites. Antibody and ON could be conjugated via different covalent and noncovalent conjugation strategies. Among them, amine conjugation, sulfhydryl conjugation, and carbohydrate conjugation are the most known three methods.

• Amine Conjugation

Antibodies contain several amino groups (NH2), which can be distributed throughout as lysine side chain epsilon-amine and N-terminal alpha-amino groups. These residues are most often targeted for conjugation as they can easily be modified owing to their steric accessibility. Besides amino groups, glutamic acid, aspartic acid residues, and carboxylic acid can also be conjugated.

• Sulfhydryl Conjugation

Antibody-ON conjugation is also possible via a reactive thiol (sulfhydryl) group. Antibodies contain oxidized sulfhydryl (-SH) groups present as disulfide (S-S) bridges and these disulfide bridges must be reduced first to expose their reactive groups by a reducing agent

• Carbohydrate Conjugation

An alternative method of site-directed conjugation can occur at carbohydrate residues, which occurs mainly in the Fc region because they are less susceptible to steric hindrance due to their remoteness from antigen-binding sites. For conjugation via this complex method, the carbohydrate group must be oxidized to an aldehyde (-CHO) using periodic acid. An advantage is that AOCs produced via site-specific conjugation techniques have distinct advantages for in vivo applications.

Fig.1 A schematic diagram of the antibody-ON conjugation process.¹

Application of AOCs

In AOC complex, the antibody is usually employed as a target recognition unit or delivery vehicle and the ON serves in a variety of functional roles such as scaffold for spatial arrangement or therapeutic drug (small interfering RNA, siRNA). AOCs have been used in numerous applications ranging from diagnostics to therapeutics and were developed through an unmet need for precise and efficient detection of low-abundance proteins. AOCs have since played a significant role in immuno-polymerase chain reaction (iPCR), proximity extension assay (PEA), electrochemical proximity assay (ECPA), DNA-PAINT imaging, and protein arrays. Based on the exceptional ability of PCR to amplify the number of DNA labels and the transformation of readily accessible ON-arrays into otherwise difficult to access antibody arrays, AOCs can largely improve the detection limits.

Our Service

AOC Development Services

Creative Biolabs takes full advantage of our featured platform to develop a portfolio of AOCs that combine the selectivity of mAbs and the precision of oligonucleotide therapy and diagnosis. Our deep experience with modulation of RNA processes, oligonucleotide therapeutics, mAb engineering and conjugation, and various drug delivery techniques provide the foundation for our efforts to promote your novel AOC development. The know-how and advanced technology born out of this experience, and their systematic application in the design and development of our product candidates, form the basis of our AOC development platform. Based on our platform, our scientists have also established a framework for screening potential cell surface protein-mAb pairs to determine which pairs we believe are well suited to deliver active ONs to specific cell types.

Our goal is to help clients discover, develop and commercialize novel AOCs that overcome current barriers to the delivery of ONs and unlock their potential to treat or diagnose diseases currently lacking adequate treatment or detection options. Based on the data-driven hypothesis that the delivery of ONs can be greatly enhanced by using antibodies as conjugates, Creative Biolabs offers high-quality AOCs development services for our global clients. If you are interested in our AOC development services, please feel free to contact us for more information.

Highlights

• Versatile AOC Platform: Supports diverse applications from drug delivery to diagnostics, leveraging robust antibody and oligonucleotide synthesis capabilities.
• Streamlined Client Support: Offers integrated AOC development services from conceptualization through to market, enhancing speed to clinical trials.
• Data-Driven Development: Employs a data-centric approach for AOC development, ensuring optimal pairing of antibodies with oligonucleotides for targeted therapeutic action.
• Advanced Conjugation Methods: Utilizes amine, sulfhydryl, and carbohydrate conjugation techniques to enhance AOC stability and efficacy for therapeutic and diagnostic uses.
• Comprehensive Development Services: Offers full lifecycle support from AOC design to commercialization, backed by extensive expertise in antibody and oligonucleotide technologies.

FAQ

1. Q: What are the primary conjugation strategies used in AOC development at Creative Biolabs?

   A: Creative Biolabs employs various conjugation strategies to attach oligonucleotides to antibodies, enhancing the specificity and stability of AOCs. The three main methods include amine conjugation targeting amino groups on antibodies, sulfhydryl conjugation via reactive thiol groups, and carbohydrate conjugation at carbohydrate residues typically found in the Fc region. These techniques ensure that AOCs are optimally designed for their specific in vivo applications.

2. Q: What makes AOCs unique in targeting diseases?

   A: AOCs uniquely combine monoclonal antibodies with oligonucleotides, targeting diseases with unmatched precision and selectivity, enabling access to previously undruggable cells.

3. Q: What are Creative Biolabs' capabilities in AOC engineering?

   A: We specialize in custom AOC design, leveraging cutting-edge conjugation methods and extensive mAb and ON therapy expertise to craft effective solutions.

4. Q: How do AOCs enhance diagnostic capabilities?

   A: AOCs improve diagnostics by significantly lowering detection thresholds for proteins, utilizing advanced PCR techniques to amplify diagnostic signals in challenging samples.

5. Q: What therapeutic roles do AOCs play?

   A: AOCs deliver therapeutic oligonucleotides directly to target cells, offering innovative treatment options for genetic and autoimmune diseases by modulating gene expression or silencing pathological genes.

6. Q: How can clients engage with Creative Biolabs for AOC development?

   A: Clients can initiate AOC development projects with Creative Biolabs by contacting our expert

Published Data

In the experiment, Antibody-Oligonucleotide Conjugates (AOCs) played a crucial role in delivering antisense oligonucleotides (ASOs) to the central nervous system (CNS) for the treatment of spinal muscular atrophy (SMA). Specifically, ASOs were conjugated to an antibody targeting the murine transferrin receptor (8D3130). This conjugation facilitated the crossing of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), enhancing the bioavailability of ASOs in the brain and spinal cord. The results demonstrated that systemic administration of 8D3130-ASO conjugates increased SMN2 splicing, which led to elevated levels of functional SMN protein in CNS and peripheral tissues, extending the survival of a severely affected SMA mouse model. This approach offers significant potential for treating neuromuscular and neurodegenerative diseases.

Fig.2 PK of antibody and antibody-PMO conjugates in mice.²