For us antibody nerds, a fascinating aspect of the development of monoclonal antibodies against coronavirus has been the debate around the role of effector function and the different approaches taken to Fc modification. Early concerns that antibodies might actually assist infectivity by the virus (antibody dependent enhancement or ADE), as can happen in diseases such as Dengue Fever, do not appear to have been realised. However, there has been no clear consensus on whether the risk of enhancing inflammation outweighs the benefit of killing infected cells, and thus whether the Fc domain should be left unmodified, engineered for enhanced effector function or engineered for reduced effector function1. The best approach may depend on the specific patient group1 or may involve selective tuning of specific effector functions2.
This developing story is only one example of the current high level of interest in the field of Fc region engineering. From a patentability perspective, this may translate into a number of different strategies for patent protection, as discussed further below.
Platform cases
Over the years, numerous patents have been filed and granted to specific mutations modifying the Fc region – for example, to reduce effector function, enhance effector function, or modify half-life by modifying binding to FcRn.
Such patents are usually directed to antibodies and Fc-fusions in general, and not limited by the identity of the antigen-binder.
While many of the individual positions of interest may now be known, scope still exists for obtaining patents to new combinations. For example, these may be combinations with particularly strong ablation/enhancement, or combinations which fine-tune the binding to particular receptors, e.g., which increase binding to activating FcγRs while decreasing binding to the inhibitory FcγIIb.
As with any invention involving the combination of known elements, it will be important that the application as filed tells a story of unexpected effects going beyond the known individual properties of the substitutions. Preferably this story will be supported by data in the application as filed.
Other “platform” approaches in this space are also possible, such as those directed to new antibody formats. For example, an interesting recent report by researchers at the Technical University of Darmstadt and Merck Healthcare KGaA describes an “Fc-tamed” format, in which the FcγR-binding sites are blocked by a masking unit to avoid off-target side effects, with the masking unit then being cleaved by a tumour-associated protease to provide on-target effector function3.
Disease-specific tuning
There are also opportunities to claim the application of known strategies for modifying the Fc region in a new context. As illustrated by the various approaches taken to COVID monoclonals, the best approach to treating a particular disease may not always be obvious. In some cases it may therefore be possible to claim a known way of modifying the Fc region in the context of a specific antigen target (as a product claim) and/or in the context of treating a particular disease (e.g., as a second medical use claim in Europe). Second medical use claims in Europe also offer the potential to protect the application of therapeutics to specific patient subpopulations, such as those with different degrees of disease severity, or those with different genetics.
It may be possible to claim the modification at a functional level (e.g., wherein the Fc modification reduces or increase the relevant function). However, it would be wise to include as many structural examples in the application as possible, particularly given the increased resistance of the USPTO to purely functional characteristics in antibody claims.
Protecting specific antibodies
Even for patent applications directed to specific antibodies (e.g., as defined by their CDRs), consideration should still be given to the role of the Fc region. If effector function is believed to play a significant role in the beneficial effect of the antibody, then ideally the application should give basis to specify the presence of an Fc region in which the relevant effector function is retained or enhanced. The application should also provide basis to specify the IgG subclass, where applicable. Where the activity relied on for inventive step depends on the presence of an effector function, an EPO Examiner may object to a claim in which this effector function is not necessarily obtained, e.g., a claim encompassing Fab fragments.
In some cases, there may be scope to make the antibody with specific Fc modifications the subject of a follow-up filing. This may have benefit in providing longer patent coverage for the commercial antibody.
Of course, choosing specific strategy will depend on the facts of each case. However, the often-unpredictable interactions between specific effector functions and disease pathology present clear opportunities to pursue patent protection for developments in this highly active area.
References
- Garber, K. Hunt for improved monoclonals against coronavirus gathers pace. Nat Biotechnol 39, 9–12 (2021)
- Atyeo et al., JCI Insight. 2021;6(1):e143129
- Elter et al., Front. Immunol., 03 August 2021
