Biparatopic Receptor-based Bispecific ADCs

Antibody-drug conjugate (ADC) represents an innovative and potent therapeutic biopharmaceutical drug. It combines the unique and sensitive targeting capabilities of antibodies allowing sensitive discrimination between healthy and cancer tissues with the cell-killing ability of cytotoxic drugs. To date, eight ADCs have been approved and more than 100 ADCs are currently in pre-clinical and clinical trials.

The key challenge during the development of a successful ADC is balancing its efficacy and safety. Bispecific antibodies presenting the ability to simultaneously engage two targets are endowing some creative possibilities to improve both the efficacy and safety of ADCs. Currently, several strategies have been developed using bispecific antibodies to enhance ADC internalization and lysosomal delivery, thereby to enhance the efficacy of ADCs, such as the bispecific and biparatopic ADCs. Creative Biolabs is a leader in the field of providing ADCs development services. We now provide a fully integrated biparatopic receptor-based bispecific ADCs design and construction services against different markers for the treatment of different cancers.

Bispecific Biparatopic Antibody

Bispecific antibodies (bsAbs) are engineered antibodies designed to recognize two different epitopes or antigens. BsAbs combine specificities of two antibodies against different antigens or epitopes that can interfere with multiple surface receptors or ligands. BsAbs offer the potential to maximize the benefits of therapeutic antibodies by various mechanisms, including simultaneously blocking two different targets or mediators that have a primary role in the disease pathogenesis, retargeting to mediate effector functions (such as antibody-dependent cell-mediated cytotoxicity (ADCC)), avoiding or delaying the development of resistance, and activating cytotoxic T and NK cells to induce tumor lysis. So far, there are more than 100 different bispecific formats endowing researchers to select the optimal parameters (such as size, half-life, stability, flexibility, orientation, and developability) to achieve the desired therapeutic outcome.

Biparatopic antibody is a subset of bispecific antibodies in which each antigen binding domain recognizes unique, non-overlapping epitopes on the same target antigen. Biparatopic antibodies have been confirmed that possess the superior ability to promote receptor clustering for improved receptor internalization, lysosomal trafficking, and receptor down regulation, therefore increasing drug potency.

Various bispecific antibodies (bsAbs) are currently in clinical development or are already approved for cancer therapy. Fig.1 Various bispecific antibodies (bsAbs). (Comer, 2018)

Bispecific Biparatopic ADCs

Recently, bispecific ADC approaches have emerged to enhance internalization and trafficking to the lysosome, thus maximizing the amount of drug that is effectively delivered to tumor cells at a given dose. Previous research suggested that targeting a single receptor with bispecific antibodies that recognize distinct epitopes could lead to increased avidity/overall affinity toward the target and greater potency. Subsequent studies confirmed that non-overlapping antibody pairs and biparatopic antibodies or non-antibody scaffolds could drive receptor clustering and cross-linking, which can enhance the internalization, trafficking to the lysosome, and degradation of the target.

By combining two non-overlapping HER2-targeted antibodies, researchers recently developed a bivalent biparatopic ADC in which the antibody has two engineered cysteines in the Fc region to enable site-specific functionalization conjugated to a potent tubulysin warhead. The ADC showed enhanced HER2 clustering and lysosomal trafficking, and potent target-mediated cytotoxic activity. Besides, the biparatopic ADC had more potent target-mediated cytotoxic activity in cancer cell lines and tumor models compared with monospecific ADC T-DM1. The biparatopic ADC also presents positive anti-tumor activity in tumor models with acquired resistance to T-DM1. Similarly, ZW49, another novel anti-HER2 biparatopic ADC that targets the same domains as trastuzumab (ECD4) and pertuzumab (ECD2) was developed. ZW49 is composed of a biparatopic antibody linked to a novel Nacyl sulphonamide auristatin payload via a protease cleavable linker. Preclinical study revealed that ZW49 can be internalized and trafficked to lysosomes in HER2-expressing cells to greater levels and faster than monospecific ADC (such as the TDM1). It also presented superior tumor growth inhibition relative to other HER2 targeted therapies in low HER2 patient-derived xenograft model and a trastuzumab-resistant high HER2 model. To date, ZW49 was selected to move forward into a phase I study.

Other biparatopic antibodies targeting different targets are also developed, which can be potentially used for biparatopic bispecific ADC development.

Schematic mechanism of action of biparatopic ADCs relying on crosslinking and clustering of receptors to enhance endocytosis and trafficking to the lysosome to deliver their payload. Fig.2 Schematic mechanism of action of biparatopic ADCs relying on crosslinking and clustering of receptors to enhance endocytosis and trafficking to the lysosome to deliver their payload. (Maruani, 2018)

Bispecific Biparatopic ADCs Development Services at Creative Biolabs

Scientists at Creative Biolabs have enriched experience in antibody development and antibody/protein-drug conjugation for more than ten years. At present, we provide a full range of biparatopic receptor-based bspecific ADCs design and development services against a variety of targets. Our best-quality services include specific antibody development, potent drug or linker-payload production, and effective bio-conjugation with unbeatable rapid turnaround times. Our biparatopic ADCs preparation services target different targets including but not limited to:

For more detailed information, please feel free to contact us or directly sent us an inquiry.

References

  1. Comer, F.; et al. Bispecific and Biparatopic Antibody Drug Conjugates. In Innovations for Next-Generation Antibody-Drug Conjugates (pp. 267-280). Humana Press, Cham. 2018.
  2. Maruani, A. Bispecifics and antibody-drug conjugates: A positive synergy. Drug Discovery Today: Technologies. 2018, 30: 55-61.

For lab research use only, not for any in vivo human use.


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