Advantages and Development Strategies of Aptamers with Low Immunogenicity

1. Root Cause of Low Immunogenicity: Chemical Nature
   Aptamers: These are single-stranded DNA or RNA molecules. Composed of nucleic acids, their chemical structure closely resembles that of naturally occurring nucleic acids in the human body (such as tRNA and microRNA). The human immune system has evolved to generally not mount strong immune responses against self-nucleic acids.

Protein/Antibody Drugs: These are exogenous proteins. Even after humanization, their amino acid sequences and spatial structures may still be recognized as “non-self” by the immune system, potentially leading to the production of anti-drug antibodies (ADAs).

2. Types and Impact of Immune Responses
   Aptamers: The likelihood of triggering an immune response is extremely low. This means:

• Fewer side effects: Reduced risks of allergic reactions, cytokine storms, etc.

• Repeatable dosing: Less likely to lose efficacy due to the production of neutralizing antibodies.

• Longer half-life: Not rapidly cleared by the immune system.

Antibody-Based Drugs: Carry the risk of inducing ADAs, which may lead to:

• Drug inefficacy: ADAs may neutralize drug activity.

• Altered pharmacokinetics: Accelerated drug clearance.

• Severe adverse reactions: Such as infusion-related reactions.

3. Optimization Strategies in Aptamer Development Services
   Specialized Aptamer Development Services employ the following design strategies to further minimize or circumvent any potential immunogenic risks:

Chemical Modifications:

• During or after the screening process (e.g., SELEX), chemical modifications (such as 2′-fluoro or 2′-O-methyl modifications) are introduced to the aptamer backbone (e.g., phosphate groups) or ribose sugars.

• These modifications not only enhance the stability of aptamers against nucleases, prolonging their in vivo half-life, but also further “disguise” the aptamers to more closely resemble naturally modified nucleic acids in the human body, making them less likely to be recognized by the immune system.

Sequence Optimization:

• Avoid specific nucleic acid sequence patterns with known immunostimulatory effects (e.g., certain CpG-rich motifs that may activate immune cells via the TLR9 pathway under specific conditions).

• Remove non-functional sequence segments that may cause nonspecific interactions through truncation and mutagenesis analysis.

Conjugation Strategies:

• Conjugating aptamers with molecules such as polyethylene glycol (PEG) or cholesterol not only increases their molecular weight and extends their half-life but also leverages PEGylation—a mature technology for reducing immunogenicity.

4. Special Cases Requiring Distinction
   Innate Immune Recognition: Under certain specific conditions (e.g., local high concentrations or particular routes of administration), some nucleic acid structures may be weakly recognized by pattern recognition receptors of the innate immune system (e.g., Toll-like receptors). However, this risk can be effectively controlled through the chemical modifications mentioned above.

Individual Variations: In rare cases, individuals with autoimmune diseases (such as systemic lupus erythematosus, where patients have anti-nucleic acid antibodies) may present unique challenges. Such scenarios require careful monitoring during clinical development.

5. Summary of Advantages
   In the context of Aptamer Development Services, low immunogenicity translates to:

• Greater safety: Higher medication safety for patients.

• More predictable efficacy: Pharmacokinetics are less likely to be disrupted by immune responses.

• Broader applicability: Suitable for chronic diseases requiring long-term or repeated dosing.

• Simplified production and storage: Nucleic acids are chemically stable and less prone to developing new immunogenic epitopes due to structural changes, unlike proteins.

Therefore, “aptamers typically elicit low immune responses in vivo” is not only one of their core advantages but also a key feature that modern aptamer development services strive to ensure and enhance through meticulous design. This makes aptamers uniquely attractive and competitive in the field of biomedicine, particularly as alternatives or complementary options to antibody-based and other protein drugs.