Megamolecule Synthetic Antibodies

• Modular synthesis permits the creation of molecules too large or complex to prepare using standard protein engineering/expression as such methods require polypeptides to be expressed as one or more chains in culture. Correct / folding and assembly and purification of larger molecules becomes more difficult as the complexity of the molecule is increased thereby decreasing yield and increasing cost. • The chemical linking strategy enables an efficient method to produce precisely-defined protein scaffolds of variable stoichiometry, orientation, and geometry. These attributes can be systematically altered by encoding diversity into the small molecule linkers and by the order of attachment. Current protein engineering methods are limited to the intrinsic repertoire of natural polypeptide folds / peptide linkers to achieve a desired construct. Therefore, non-natural formats that may exhibit greater efficacy cannot be prepared using conventional engineering methods. • The mild, rapid, and site-specific nature of the linking reactions allows for diverse effector molecules to be attached to an antibody fragment in precise stoichiometry in high yield and away from the antibody-like fragment. Current chemical methods require the engineering of a reactive amino acid or the use of a preexisting reactive amino acid side chain to attach payloads to the antibody scaffold. In many cases, products of these reactions yield heterogeneous populations of products. Therefore, such reactions must be arduously optimized prior to scale-up. Such direct amino-acid modifications may also not be stable or cause deleterious effects to the pharmacological properties of the parent molecule (e.g. increased hydrophobicity, aggregation, immunogenicity, etc.) therefore a great deal of effort must be directed toward choosing a suitable location for attaching the payload. • The modularity of the linking reactions also enables the joining of effector molecules (e.g. toxins, glycosylated proteins) that cannot be produced in one culture system efficiently due to toxicity constraints or metabolic profiles of the expression hosts.

A novel method to join antibody fragments to produce megamolecule antibody like drugs #therapeutics #antibody

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