Binding molecules

What is this patent about?

’524 is related to the field of genetic engineering and immunology, specifically the production of therapeutic antibodies. Traditional monoclonal antibodies are complex tetramers requiring both heavy and light chains, which complicates manufacturing and limits their use in multi-specific formats. This invention addresses the need for high-affinity, soluble, heavy chain-only antibodies (HCAbs) that can be produced in transgenic animals and easily engineered for diverse clinical applications.

The underlying idea behind ’524 is that a transgenic mouse can be programmed to generate a diverse repertoire of fully functional, humanized heavy chain-only antibodies by utilizing a modified immunoglobulin locus. By explicitly removing the CH1 domain from the heavy chain constant regions, the invention bypasses the biological requirement for light chain association. This allows the animal’s own immune system to perform VDJ recombination and somatic hypermutation on human variable segments, resulting in high-affinity binding domains that are naturally soluble and stable as monomers.

The claims of ’524 focus on a method for producing soluble, antigen-specific heavy chain-only antibodies using a transgenic mouse equipped with a heterologous VH heavy chain locus. The process involves immunizing the mouse to trigger the natural immune response, followed by cloning the resulting antibody sequences from antibody-producing cells. The independent claim specifically requires that the locus contains at least one naturally occurring human VH segment and constant regions that lack a functional CH1 domain, ensuring the production of antibodies that have undergone affinity maturation.

In practice, the invention works by leveraging the mouse's internal cellular machinery to refine the human VH domains in response to a specific antigen challenge. Once the mouse produces these specialized antibodies, the genetic sequences for the most effective binders are isolated and cloned. These clones can then be expressed in various systems—such as mammalian cell cultures, bacteria, or yeast—to manufacture either the full heavy chain-only antibody or just the isolated VH binding domain.

This approach differentiates itself from prior methods by combining the benefits of in vivo selection with the structural simplicity of single-domain antibodies. Unlike phage display libraries, which often produce low-solubility domains that require extensive engineering, this method utilizes the mouse’s somatic mutation process to naturally select for high-affinity, soluble binders. Furthermore, by eliminating the CH1 domain across different antibody classes, the invention enables the production of diverse isotypes like IgG and IgM without the manufacturing hurdles associated with light-chain mispairing.