Eliminating Antibody Products

Introduction

Conventional monoclonal antibodies, while vital in therapeutics, face significant limitations when targeting soluble antigens, primarily due to antibody-mediated antigen accumulation. This occurs because the antibody-antigen complex is recycled by the neonatal Fc receptor (FcRn), extending the antigen's half-life and necessitating impractical high dosages. To address this, Creative Biolabs offers eliminating antibody, an advanced modality engineered to actively eliminate soluble antigens from circulation. This innovative approach significantly reduces required dosages and expands the range of druggable targets, offering a powerful solution for challenging therapeutic areas.

Advantages of Eliminating Antibody

Eliminating antibody offer distinct advantages over traditional antibody types, fundamentally changing how soluble antigens are targeted:

• Active Antigen Elimination: Unlike conventional antibodies that simply bind to an antigen and can lead to its accumulation in plasma, eliminating antibodies actively eliminate soluble antigens from circulation. This is achieved by increasing the cellular uptake of the antibody-antigen complex into endosomes, where the antigen is then dissociated and degraded in lysosomes.
• Reduced Dosage and Dosing Frequency: The active clearance mechanism of eliminating antibodies means that a single antibody molecule can clear multiple antigen molecules over time. This multi-turnover binding significantly reduces the required antibody dosage (e.g., over 30-fold reduction compared to conventional antibodies). This reduction is critical for enabling convenient subcutaneous injection and less frequent dosing regimens, dramatically improving patient quality of life and reducing healthcare costs.
• Targeting High Concentration Antigens: Eliminating antibodies can effectively neutralize soluble antigens present at very high plasma concentrations, where conventional antibodies, even with infinite affinity, are completely ineffective or require impractical dosages. This opens up new therapeutic possibilities for targets previously considered "undruggable" due to their high abundance.
• Improved Pharmacokinetics Profile: The Fc engineering component of eliminating antibodies can be designed to maintain favorable antibody pharmacokinetics while enhancing antigen clearance. Even when modifications increase antibody clearance to some extent, the overall effect is a more efficient reduction of the target antigen in plasma.
• Antagonism of Multi-Epitope or Toxic Antigens: Eliminating antibodies can effectively antagonize antigens with multiple functional epitopes or even toxic antigens that lack defined functional epitopes, by directly removing them from circulation. This capability extends beyond the neutralizing capacity of conventional antibodies, which can only target specific functional epitopes.

Fig. 1 Antigen sweeping by pH-sensitive antibody with increased FcRn binding at neutral pH.^{1, 3}

Applications of Eliminating Antibody

Creative Biolabs's eliminating antibody are applicable across a wide range of research and clinical areas, particularly where conventional antibody approaches fall short due to soluble antigen challenges:

• Treatment of Complement-Mediated Diseases: Eliminating antibodies have shown significant promise in targeting complement component 5 (C5), a soluble antigen present at high concentrations in human serum. For instance, engineered anti-C5 eliminating antibodies have demonstrated enhanced C5 clearance and long-lasting neutralization, addressing the high dosage and frequent administration issues of conventional therapies.
• Neutralization of Toxins and Pathogens: Eliminating antibodies can be highly effective against soluble toxins, such as Staphylococcal enterotoxin B (SEB) superantigen, by accelerating their elimination from circulation, even if they don't possess direct neutralizing activity in vitro. This provides a novel approach for developing antitoxins when neutralizing antibodies are unavailable.
• Management of Shed Antigens: For antigens that are shed from cell membranes into circulation (e.g., CEACAM-5 in tumors), eliminating antibodies can reduce their systemic concentration, thereby allowing better targeting of the cell-bound antigen in diseased tissues.
• Addressing Antibody Pharmacokinetics Issues: Eliminating antibodies are particularly beneficial for soluble antigens that cause rapid clearance of antibody-antigen complexes, like PCSK9. Recycling variants have substantially improved PCSK9 antibody pharmacokinetics, potentially enabling less frequent or lower dosing schemes.
• Cancer Immunotherapy Enhancement:
  • Direct Antigen Elimination in Tumors: For soluble antigens or those highly concentrated in the tumor microenvironment (TME) (e.g., VEGF in brain cancer, IL-6 in tumors) , eliminating antibodies can actively reduce their local concentration, enhancing therapeutic effect.
  • CAR-T Cell Engineering: pH-responsive antibody fragments can be integrated into Chimeric Antigen Receptors (CARs) to create "Conditionally Active Biologics (CAB)-CAR-T cells." These engineered T cells are designed to activate only under the acidic conditions of the TME, reducing on-target, off-tumor toxicities and improving precision in solid tumor treatment.

Fig. 2 The trafficking mechanism for a conventional and pH-sensitive antibody.^{2, 3}

• Improved Drug Delivery Across the Blood-Brain Barrier (BBB): pH-responsive antibodies targeting internalizing receptors on brain endothelial cells, such as the Transferrin receptor (TfR), can facilitate drug transport across the BBB. By dissociating their payload in the acidic endosomes, these antibodies can enhance brain exposure of therapeutic agents and allow the receptor to recycle, overcoming limitations of conventional delivery methods.

Workflow of Eliminating Antibody Product Customization

Creative Biolabs's comprehensive workflow for Eliminating Antibody Product customization is designed for clarity and efficiency, ensuring tailored solutions for your specific needs.

• Project Consultation and Design

Initial in-depth discussion with Creative Biolabs's R&D specialists to understand your specific project goals, target antigen characteristics, and desired therapeutic profile. Based on this, we strategize the optimal eliminating antibody design, considering variable region engineering (pH-dependent binding) and Fc engineering (enhanced cellular uptake and desired pharmacokinetics).

• Variable Region Engineering for pH-Dependent Binding

We employ advanced protein engineering techniques to introduce pH-dependent binding properties. This often involves histidine mutagenesis in the CDRs and/or framework regions of your existing antibody lead, or de novo screening from specialized synthetic libraries. We optimize for strong binding at neutral pH (plasma) and efficient dissociation at acidic pH (endosome).

• Fc Region Engineering for Enhanced Cellular Uptake and PK

We introduce specific mutations into the Fc region to either increase FcRn binding at neutral pH or selectively enhance Fc receptor binding. Simultaneously, we fine-tune mutations (e.g., N434A) to maintain or prolong desirable antibody pharmacokinetics and minimize potential issues like immunogenicity or altered protein A binding.

• In vitro Validation and Characterization

Comprehensive in vitro testing of the lead eliminating antibody candidates. This includes detailed binding kinetics at various pH levels, assessments of immune complex formation, confirmation of antigen dissociation in acidic environments, and evaluation of cellular uptake efficiency.

• In Vivo Efficacy and Pharmacokinetics Assessment

Evaluation of the lead candidates in relevant preclinical animal models (e.g., human FcRn transgenic mice, cynomolgus monkeys) to confirm active antigen elimination, assess dosage reduction potential, and characterize antibody pharmacokinetics and pharmacodynamics. Studies may include co-injection models or steady-state models to mimic therapeutic situations.

Why Choose Us?

Creative Biolabs is at the forefront of antibody engineering, providing unparalleled expertise in the development of eliminating antibody. Our commitment to scientific rigor, innovative solutions, and client success sets us apart.

• Pioneering Expertise: Our team comprises specialists with over 20 years of experience in advanced antibody engineering, including pioneering work in pH-dependent and eliminating antibody modalities. This deep scientific knowledge is directly integrated into our eliminating antibody product development.
• Proven Track Record: Our researchers have consistently published in high-impact scientific journals, detailing successful engineering of eliminating antibodies that demonstrate significant antigen reduction in preclinical and clinical models. Our clients experience an average 75% increase in antigen clearance efficacy and a 50% reduction in required dosage.
• Integrated Engineering Approach: We master both variable region engineering for precise pH-dependent binding and sophisticated Fc engineering for optimized cellular uptake and pharmacokinetic profiles. This holistic approach ensures a truly optimized eliminating antibody.
• Predictive Preclinical Models: We utilize advanced in vivo models, including human FcRn and human Fc receptor transgenic mice, and cynomolgus monkeys, to provide highly predictive data for human translation, reducing risks in later clinical stages.

FAQs About Eliminating Antibody

1. What types of antigens are most suitable for Creative Biolabs's Eliminating Antibody? Our eliminating antibody are particularly well-suited for soluble antigens that are present at high concentrations in plasma or in local diseased tissues, or those that cause rapid clearance of conventional antibody-antigen complexes. This includes targets like complement proteins, certain cytokines, growth factors, and toxins.
2. How do Creative Biolabs's eliminating antibodies compare to traditional affinity-enhanced antibodies? While affinity maturation improves binding, traditional high-affinity antibodies still lead to antigen accumulation because the complex is recycled. Our eliminating antibodies go beyond by actively eliminating the antigen from circulation through pH-dependent dissociation and enhanced cellular uptake. This allows for superior antigen reduction and significantly lower dosing, a feat conventional affinity-enhanced antibodies cannot achieve.
3. Can your Eliminating Antibody technology be applied to non-neutralizing antibodies or multi-epitope targets? Absolutely! One of the remarkable advantages of our eliminating antibody is their ability to exert in vivo efficacy by directly sweeping the target antigen, even if the antibody has no in vitro neutralizing activity. This makes them ideal for multi-epitope antigens where neutralizing all epitopes is challenging, or for toxins that lack functional epitopes.
4. What level of dosage reduction can I expect with an Eliminating Antibody Product? The exact dosage reduction depends on the specific antigen and desired therapeutic effect. However, our internal studies and published data have demonstrated dramatic reductions, ranging from 50-fold to over 1000-fold lower plasma antigen concentrations compared to conventional antibodies, enabling significantly lower and less frequent dosing regimens.
5. How does Creative Biolabs address potential off-target effects or immunogenicity with eliminating antibodies? We employ rigorous Fc engineering strategies, carefully selecting mutations that enhance Fc receptor binding while minimizing unwanted interactions or immunogenicity. Our comprehensive in vitro and in vivo characterization includes assessments of off-target binding and safety parameters to ensure the developability and clinical viability of our eliminating antibody.

Creative Biolabs's eliminating antibody represent a significant leap forward in therapeutic antibody development. By actively clearing soluble antigens from circulation, our engineered antibodies offer unprecedented advantages in terms of dosage reduction, expanded target applicability, and enhanced in vivo efficacy. With our profound scientific expertise and state-of-the-art engineering capabilities, Creative Biolabs is your trusted partner in bringing innovative biologic therapies to patients. Contact us for more information and to discuss your project.

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