Biparatopic Antibody (bpAb) Products

Introduction

Biparatopic antibodies (bpAbs) are a sophisticated class of engineered antibodies that uniquely bind to two distinct, non-overlapping epitopes on a single molecular target. This differentiated binding mode allows for novel mechanisms of action (MoAs) that extend beyond those achievable with conventional monospecific or even traditional bispecific antibodies. Recent breakthroughs, including the first approval for a bpAb in HER2-positive biliary tract cancer, underscore their immense therapeutic potential. Creative Biolabs is leading the way in this innovative field by providing advanced bpAb solutions.

Advantages of Biparatopic Antibody

Biparatopic antibodies offer distinct advantages over traditional antibody formats, driven by their unique dual-epitope binding capability:

• Increased Affinity and Avidity: By simultaneously engaging two distinct epitopes on the same target, bpAbs exhibit superior binding affinity and slower dissociation rates compared to monoparatopic antibodies. This avid binding enhances target engagement and can lead to more potent therapeutic effects.
• Receptor Clustering and Downregulation: Biparatopic binding can induce the formation of higher-order receptor-antibody clusters on the cell surface. This clustering often leads to rapid receptor internalization and subsequent lysosomal trafficking, effectively downregulating the target protein. This mechanism is particularly beneficial for therapeutic strategies aiming to remove disease-driving receptors.
• Enhanced Therapeutic Effects: By inducing unique clustering, bpAbs can significantly amplify immune effector functions, including CDC, ADCC, and ADCP. This potentiation of immune responses contributes to stronger anti-tumor activity.
• Novel Agonism and Antagonism: The bpAbs can promote strong agonism for receptors that rely on cross-linking for efficient downstream signaling, enabling activation in cases where conventional antibodies might fail. Conversely, through precise engineering, bpAbs can be designed to lock target conformations into an inactive state or induce 1:1 binding, effectively converting an agonist into a potent antagonist by preventing unwanted clustering and signaling.
• Overcoming Resistance Mechanisms: In infectious diseases, bpAbs can prevent mutational escape by targeting multiple epitopes simultaneously, ensuring broader and more durable neutralization. In oncology, multi-epitope targeting can also prevent tumor escape mechanisms.

Fig. 1 Biparatopic antibodies bind to two distinct epitopes of the same antigen.¹

Applications of Biparatopic Antibody

Based on versatile mechanisms, Biparatopic antibodies has been used in both research and clinical development.

• Cancer Treatment: The majority of bpAbs currently in development target oncology indications. Their ability to induce potent receptor internalization, downregulation, and enhanced immune effector functions make them highly effective against various cancers. Notably, bpAbs targeting HER2 are a prominent area of focus, building on the success of dual epitope targeting strategies.
• Antibody-Drug Conjugates (ADCs): The bpAbs are increasingly utilized as advanced platforms for ADCs. Their unique ability to promote rapid internalization and lysosomal trafficking ensures efficient delivery of cytotoxic payloads directly to tumor cells, even at low receptor densities, leading to superior payload delivery compared to monoparatopic agents.
• Cellular Immunotherapies (CAR-T, T-cell Engagers): The high affinity and selectivity of bpAbs are highly attractive for engineering next-generation T-cell recruiters and Chimeric Antigen Receptor (CAR) T-cell therapies. The success of the first bpAb-based CAR-T therapy for multiple myeloma highlights their enhanced and sustained efficacy in cell therapy.
• Infectious Disease: The bpAbs are poised to transform the treatment of viral infections by providing broadly neutralizing antibodies that overcome mutational escape variants. By targeting multiple epitopes on viral proteins, bpAbs offer sustained efficacy against diverse viral landscapes, as demonstrated in preclinical and clinical studies for SARS-CoV-2 and HIV.
• Enzyme Inhibition and Receptor Modulation: Beyond oncology and infectious diseases, bpAbs can act as potent enzyme inhibitors by locking extracellular domains in catalytically inactive states or stimulating multi-component receptor complexes. This precision modulation expands their utility to a variety of other therapeutic targets.
• Functional Assays and Research Tools: The ability to precisely control complex formation and signaling makes bpAbs invaluable tools for fundamental research into receptor biology and signal transduction mechanisms.

Fig. 2 The Biparatopic Antibody Causes Strong HER2 Internalization.²

Our Biparatopic Antibody Customization Service

Creative Biolabs' biparatopic antibody customization service follows a comprehensive and transparent workflow, designed to deliver optimal results for your specific project.

• Epitope Identification and Selection: Our expert team will analyze your target protein to identify novel, non-overlapping epitope pairs crucial for biparatopic engagement. This involves leveraging advanced computational tools and our extensive proprietary epitope databases. For complex targets like CD30 with duplicated regions, we employ precise epitope determination strategies using ortholog screening and mutant analysis.
• Parent Antibody Discovery and Engineering: We will either utilize existing parent antibodies (e.g., scFv, Fab) or initiate novel antibody discovery campaigns (e.g., phage display) to generate high-affinity binders to the selected epitopes. These individual binding domains are then engineered for optimal compatibility within the biparatopic format, often involving rigorous affinity and specificity characterization.
• Biparatopic Construct Design and Optimization: Our specialists design various bpAb formats (e.g., tandem scFv, scFv×Fab, Fc-containing asymmetric designs) based on target biology and desired function. Crucially, we focus on rational linker design, determining optimal length (e.g., GS linkers, PAS linkers) and composition, which is critical for controlling complex stoichiometry (1:1 binding vs. multimeric clustering) and functional outcomes. This phase often involves in-silico modeling and structural analysis (e.g., Cryo-EM) to predict and optimize interactions.
• Expression, Purification, and Biophysical Characterization: Selected bpAb constructs are expressed in appropriate systems (e.g., mammalian cells, E. coli) and purified to high homogeneity. Extensive biophysical characterization is then performed, including binding kinetics and affinity (SPR and ITC for precise K_D, k_on, k_off measurements).
• Functional Validation and Mechanism of Action Studies: Comprehensive in vitro functional assays are conducted to validate the desired MoA (e.g., receptor activation/inhibition, internalization, immune effector function, ligand blocking). For instance, we can demonstrate the conversion of an agonistic bpAb to an antagonist by showing a shift from cluster formation to 1:1 complex binding.

Fig. 3 Epitope binning-based FACS screening and the production of a biparatopic antibody.¹

FAQs of Biparatopic Antibodies

• How do biparatopic antibodies differ from traditional bispecific antibodies? Unlike most bispecific antibodies that target two different molecules or cell types, biparatopic antibodies (bpAbs) uniquely bind to two distinct, non-overlapping epitopes on the same target molecule. This unique binding mode allows for differentiated mechanisms of action like enhanced receptor clustering, precise control over agonism/antagonism, and improved internalization, offering distinct therapeutic advantages.
• Can your biparatopic antibody services help with drug resistance? Absolutely! A key advantage of bpAbs is their potential to overcome resistance mechanisms. In infectious diseases, targeting multiple epitopes can prevent mutational escape that renders single-target therapies ineffective. In oncology, multi-epitope targeting can also address tumor escape mechanisms, leading to more durable responses.
• What types of targets are best suited for biparatopic antibody development? BpAbs are highly versatile! They are particularly well-suited for targets where enhanced receptor clustering, precise modulation of signaling (agonism or antagonism), or superior internalization is desired. This includes various cell surface receptors (e.g., TNFRSF members like HER2, CD30) and viral coat proteins.
• How do you ensure the stability and manufacturability of biparatopic antibodies? Creative Biolabs employs rigorous design principles and advanced engineering techniques to ensure the stability and manufacturability of our bpAbs. This includes careful selection of parent antibody fragments, rational linker design and optimization, and comprehensive biophysical characterization early in the development process. Our proprietary production methods also contribute to high homogeneity and yield. Ask us about our developability assessment services!
• Is it possible to convert an existing agonistic antibody into an antagonist using bpAb technology? Yes, this is one of our most exciting capabilities! It demonstrates that by precisely engineering the bpAb format, particularly through strategic epitope pairing and linker design, The agonistic antibodies can be converted into effective, 1:1-binding antagonists that block unwanted signaling without inducing activation. This opens new avenues for repurposing and optimizing existing therapeutic assets.

Creative Biolabs stands at the forefront of biparatopic antibody (bpAb) innovation, offering unparalleled expertise and a proven track record in engineering these sophisticated molecules. Our commitment to scientific excellence and client success differentiates us. Creative Biolabs' bpAb solutions offer novel strategies for your most challenging therapeutic programs. Contact us for biparatopic antibody products or for more Information to support your project.

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