Bispecific/Multispecific Antibodies: The Common Light Chain and Upper Hand of Humanized Avian Antibodies
Common light chain strategies simplify bispecific IgG assembly across multiple heterodimeric formats by eliminating light chain mispairing and reducing molecular heterogeneity
Bispecific and Multispecific Antibody Formats
Image adapted from Bergholz et al. (2021) Cancer Res
Past decades of research have uncovered deep insights into the biology of diseases and their associated pathways. Antibodies have gained traction in parallel, and are recognized as highly specific therapeutics that can be designed and adapted for personalized therapy. However, as researchers demonstrate the incredible complexity of pathways underlining common diseases, in some cases, monospecific antibodies have encountered limitations. At Immune Biosolutions, we’re ready to partner with clients to create next-generation biologics.
Why Bispecific and Multispecific Antibodies
Aside from the engagement of the immune system through a CD3 or CD8 T-cell engager arm, these new formats also aim to circumvent the resistance of monospecific antibodies in cancer. Most commonly, monospecific antibodies allow single-pathway blockade by targeting a single protein. Therapeutic resistance happens when a treatment loses its effectiveness, which has been observed in some cancers following the use of monoclonal antibody treatment. This resistance can stem from many factors linked to the patient or the pharmacokinetic of the molecules themselves but can also be the result of compensatory mechanisms in cancer cells. Molecular pathways of the immune system are incredibly complex, and sometimes redundant. This can lead to reduced effectiveness of a pathway blockade in virtually any cell type, but cancer cells are especially ingenious in adapting and rewiring immune pathways to circumvent disruptions (Bergholz et al. (2021) Cancer Res).
The Avian Common Light Chain Advantage: Clean Developability and Manufacturing
Design considerations to allow for proper biological targeting and good developability are crucial. Many bispecific and multispecific formats require a common light chain to optimize construction assembly and developability. In mammals, this can be challenging, but in chickens, finding common light chains is straightforward.
Chickens have one functional light chain, and because diversity happens mostly through gene conversion, not V(D)J recombination, frameworks are highly conserved which favors structural compatibility across different heavy chains. This makes avian-based biologics uniquely suitable for the development of bi- and multispecific antibodies. Here’s two of many examples of antibody formats for which a common light chain is ideal:
Knob-Into-Hole
Knob-into-hole bispecifics are a popular format for bispecific antibodies, which feasibility is often largely impacted by light chain mispairing.
Trispecific and Multispecific Antibodies
In trispecific and multispecific antibodies, common light chain strategies become increasingly important, as they collapse combinatorial heavy-light pairing complexity and enable scalable manufacturing of structurally defined molecules. A common light chain allows for a simplified pipeline and reduced costs.
Some Other Formats We Can Optimize for You
IgG-scFv
scFv-scFv
Antibody Fusion Protein
Visit our website and contact our team to learn more about avian antibodies and to discuss a custom approach to your bispecific and multispecific antibody projects.
References
Bergholz JS, Zhao JJ. How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer. Cancer Res. 2021 Dec 15;81(24):6074-6077. doi: 10.1158/0008-5472.CAN-21-3605. PMID: 34911779; PMCID: PMC9033251.
Herrera M, Pretelli G, Desai J, Garralda E, Siu LL, Steiner TM, Au L. Bispecific antibodies: advancing precision oncology. Trends Cancer. 2024 Oct;10(10):893-919. doi: 10.1016/j.trecan.2024.07.002. Epub 2024 Aug 30. PMID: 39214782.
