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Approaches to Antibody Engineering
The gold standard method of monoclonal antibody (mAb) production is a recombinant approach, which reduces the need for animal involvement and increases the consistency between production lots of the antibody. In recent years, the discovery and manufacturing of small non-canonical antibody types, such as variable heavy domain of heavy chains (VHH), have also enabled new avenues of research. These single-domain antibodies (sdAbs) offer significant benefits due to their small size, high affinity and stability, low immunogenicity, good solubility, and enhanced tissue penetration.
The cumulative effect of these advancements has resulted in a new generation of enhanced mAbs and VHH, now positioned at the leading edge of diagnostics and therapeutics.
Antibodies for Therapeutics
Due to their ability to closely target some cancer cell surface proteins without the systemic drawbacks of standard chemotherapy, mAb therapies are widely used in cancers that express known targets like EGFR and HER2. Antibody therapies are also well established for treating infectious diseases and autoimmune disorders like inflammatory bowel diseases, type 1 diabetes mellitus, and multiple sclerosis.
To enhance efficacy and reduce risk of drug resistance and toxicity from combination therapies, bispecific antibodies are engineered to target two antigenic epitopes. By performing two functions in one molecule—binding tumor cells and recruiting cytotoxic immune cells, for example—bispecific antibodies can do more with less drug and potentially fewer side effects.
Bispecific antibodies can be either IgG-based or fragment-based. The known advantages of VHH, including increased solubility and thermal stability, can be harnessed into bispecific or even trispecific VHH, in which two or three VHH domains are connected by a flexible peptide linker. Multispecific VHH are undergoing investigation for treatment of solid tumors and conditions like psoriatic arthritis and psoriasis.
Advances in antibody engineering have enabled more precise payload targeting, allowing for highly specific therapies that deliver treatments directly to disease sites. Beyond standard mAb treatment, antibody-based therapy has expanded to include other types of drug products, such as antibody-drug conjugates (ADCs). ADCs combine a mAb with a cytotoxic payload and a linker that releases the payload once inside a tumor cell.
For the treatment of hematological malignancies, chimeric antigen receptor T-cell (CAR-T) therapy provides new second- or third-line treatment options for some patients. Six CAR-T therapies have been approved in the U.S., and most of these use single-chain fragment variables (scFvs) as targeting domains. However, use of scFvs for CAR-T engineering may have limitations, such as the potential for folding instability and changes in binding affinity when engineered into a CAR using a linker. To overcome some of these issues, VHH are being explored for numerous CAR-T therapies and offer advantages in stability, low immunogenicity, binding affinity, and modularity that could lead to improvements in CAR-T efficacy.
Immunohistochemistry for Companion Diagnostics
Multiplex immunofluorescence (mIF) is a specialized type of immunohistochemistry (IHC) that addresses the need in personalized medicine to assess multiple biomarkers simultaneously. Using fluorescently labeled antibodies, mIF can detect up to 40 or more biomarkers simultaneously, reducing the need for tissue and enhancing the amount of diagnostic and prognostic information that can be obtained. IHC is used in several FDA-approved companion diagnostics to help select appropriate mAb therapies.
Conclusion
At Fortis, we believe that your research deserves more than a one-size-fits-all approach—it deserves a partner who empowers you. Our recombinant monoclonal antibody and VHH development services and spatial biology CRO services are supported by a team with over 50 years of experience.
Let us craft a project plan that meets your unique needs.
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