Bispecific Antibodies and Antibody Drug Conjugates: More Complex and Targeted Biologic Therapeutics
With the maturation of monoclonal antibodies (mAbs) based cancer immunotherapy drugs that target specific, actionable biomarkers, the biopharmaceutical industry has been developing more complex mAbs, such as bispecific antibodies and antibody drug conjugates. The Business Research Company projects the global monoclonal antibody market will exceed USD 170 billion by 2025 at a 12.9 percent CAGR. And in Asia, several companies are leading the way with these advanced antibody drug pipelines, including Astellas and Daiichi Sankyo in Japan, Adpro in Korea, and Miracogen in China.
Earlier in May, the FDA approved the 100th monoclonal antibody product, marking a significant milestone for this technology. The storied successes of the anti-PD-1 and anti-PD-L1 immune checkpoint inhibitor drugs have proven that mAbs demonstrate an excellent ability to recognize cell-surface receptors on cancer cells.
Monoclonal antibodies can be further enhanced by delivering cytotoxic cells or payloads to their intended target. Bispecific antibodies and antibody drug conjugates are two techniques that achieve this goal and are intensely investigated regarding their binding kinetics, stability, and immunogenicity as clinical trials move towards approval.
Bispecific antibodies are a relatively new class of targeted antibody therapeutics that can bind to two different antigens. There are over 150 bispecific antibodies in clinical pipelines, ranging from small monovalent binding fragments to IgG-like larger molecules. Asides from cancer, they are also studied for the treatment of osteoporosis, hemophilia, and autoimmune diseases.
Picture 1. Mechanism of action of catumaxomab, showing the bispecific regions binding to a tumor cell receptor and a T cell receptor. The Fc region is additionally bound to a Fc receptor. Source: Catumaxomab – Wikipedia
The double specificity means that these special antibodies can bind to cancer cells and can also bind to other cells, most commonly to T-cells. Theoretically, this method is superior as it allows for three mechanisms of action, as compared to the one or two mechanisms of action for regular monoclonal antibodies.
Antibody drug conjugates (ADCs) are a class of therapeutics that co-leverages the selectivity of antibodies and the cytotoxicity of small molecule drugs, creating a payload delivery system that is more targeted and precise than traditional methods. This class of therapeutics has received significant interest since it was first synthesized decades ago, given its promise of delivering potent payloads at small quantities and minimizing the side effects to the patient. All but three of the ten FDA-approved ADCs have come in the past four years.
Picture 2. A simple representation of antibody drug conjugates in action, with a monoclonal antibody – linker – cytotoxin drug conjugation, attached to cancer cells. Source: Expanding the Horizon of Antibody-Drug Conjugates for Cancer Treatment
Antibody drug conjugates are manufactured by attaching the cytotoxic drug to the monoclonal antibody with a linker. Linkers are made of short-chained structural motifs such as peptides or disulfides. The ADC can either have a non-cleavable linker, where the entire system is the drug, or a cleavable linker, which allows enzymes in the cancer cells to separate the cytotoxic payload upon delivery.
With several approvals in oncology, ADCs have a bright future ahead, with several small biotechs expanding the payload-delivery potential to autoimmune diseases such as rheumatoid arthritis or even to deliver antibiotics.
Binding affinity and kinetics are a set of parameters that describe how strongly a protein binds to its ligands, and how fast a protein binds and unbinds to its ligands. Due to their more complex structure, both bispecific antibodies and antibody drug conjugates bring new challenges when understanding their binding affinity and kinetics.
When considering bispecific antibodies, the interdependence of their two antigen binding sites, plus the Fc region, make it important to have specific assays and data processing techniques that account for bivalent analytes. While when considering ADCs, even minor changes to the conjugations and linkers have been shown to alter the binding kinetics of the protein-ligand binding events, and therefore make full characterization important in both the development of the conjugation chemistry and in drug development.
Surface Plasmon Resonance (SPR) and Isothermal Calorimetry (ITC) are two complementary protein-ligand binding assay techniques that address these challenging antibodies. SPR is the gold standard label-free kinetics tool and ITC is the gold standard label-free affinity tool.
It is useful to measure using the SPR and ITC techniques for the following:
- Binding affinity under native conditions
- Binding kinetic on-rates and off-rates
- Screening for potential candidates
- Epitope-mapping and epitope-binning
- Measuring immunogenic response from anti-drug antibodies (ADA)
- Characterizing bivalent interaction of two antigen binding sites in bispecific antibodies
- Characterizing drug-linker conjugates
- Comparability studies
For all stages of drug discovery and development for advanced monoclonal antibodies, characterization techniques such as SPR and ITC play a vital role in determining the safety and efficacy of candidates.
Click the links below to learn more about our offerings and talk to one of our many specialists to learn how we can help you characterize bispecific antibodies and antibody drug conjugates.
Other biophysical characterization techniques available at DKSH include: DLS, Flow Imaging Microscopy, SEC-MALS, DSC, NTA, QCM-D, switchSENSE DNA Nanolevers, and Nano Flow Cytometry
Sources:
- Global Monoclonal Antibodies (Mabs) Market Data And Industry Growth Analysis
- Bispecific antibodies Archives – The Antibody Society
- FDA modifies immunogenicity language in final bispecific antibody guidance | RAPS
- How Next Generation ADCs Expand Beyond Cytotoxic Payloads
- Charting the choppy history of ‘magic bullet’ antibody-drug conjugates
- Impact of linker and conjugation chemistry on antigen binding, Fc receptor binding and thermal stability of model antibody-drug conjugates
About the Author
James Hsu joined DKSH in 2019 as Business Development, DKSH Technology. In this role, he is responsible for growing the life sciences and scientific solutions business. His previous experience was accumulated in the bustling Asian genomics and proteomics sector, where he worked on bringing a digital PCR startup to market. James graduated from the University of California, San Diego.
James Hsu
Life Science
