Subtypes of humanized antibody against interleukin-6 receptor

What is this patent about?

’800 is related to the field of recombinant antibody production and the characterization of molecular variants that arise during the manufacturing of therapeutic proteins. Specifically, it addresses the identification and clinical use of specific subtypes of the humanized PM-1 antibody, which targets the interleukin-6 receptor (IL-6R) to treat inflammatory and autoimmune disorders. While recombinant technology aims for uniform protein sequences, post-translational modifications often create structural variants that must be characterized to ensure pharmaceutical consistency and efficacy.

The underlying idea behind ’800 is that specific C-terminal modifications of the antibody heavy chain—specifically the loss of a terminal glycine and the subsequent amidation of the proline residue at position 447—result in stable, functional antibody subtypes. The inventors discovered that these modifications can occur on either one or both heavy chains of the PM-1 antibody without compromising the molecule’s ability to bind to its target or inhibit cell growth. This insight allows for the formal inclusion of these naturally occurring variants in pharmaceutical compositions, ensuring that the therapeutic profile remains robust even when these specific isoforms are present.

The claims of ’800 focus on methods for inhibiting IL-6R activity and treating conditions like rheumatoid arthritis using specific antibody subtypes characterized by C-terminal amidation. The independent claims cover three primary configurations: a subtype where only one heavy chain is amidated at Pro-447, a subtype where both heavy chains are amidated, and compositions that combine these two variants. These claims explicitly require the heavy chains to feature a pyroglutamylated N-terminal glutamine and a specific light chain sequence, defining the precise molecular architecture of the therapeutic agent.

In practice, these subtypes are generated during the cultivation of host cells, such as CHO cells, particularly when using specific growth media like those containing fish meat-derived peptones. The invention utilizes liquid chromatography and mass spectrometry to isolate and verify these variants, confirming that the terminal glycine (position 448) is removed and the remaining proline is converted to Pro-NH2. This rigorous characterization ensures that the resulting pharmaceutical product meets strict quality standards while acknowledging the inherent heterogeneity of biological manufacturing.

This approach differs from prior art by identifying and validating specific, functional isoforms of the PM-1 antibody that were previously uncharacterized. Rather than viewing these variants as impurities or degradation products, the invention demonstrates that the amidated subtypes retain full biological potency, including antigen-binding and cell growth-inhibiting activities, identical to the native sequence. By defining these specific C-terminal modifications, the patent provides a clear framework for utilizing these variants in the treatment of chronic inflammatory diseases like juvenile idiopathic arthritis.