Diversity of Fc Effector Function in Antibody-Based Therapeutics
Geoff Hale, PhD, CEO, mAbsolve
Antibody Science Advances Expanding R&D Pipelines
Advances in antibody science are generating a greater diversity of immunoglobulin-based therapies, which are poised to significantly expand the market in the next few years.
mAbsolve CEO Geoff Hale spoke about the R&D revolution at the Antibody Engineering and Therapeutics Europe conference in June, citing recent changes to naming conventions as evidence of the surge in activity in the field.
“Antibodies, which get into advanced clinical trials, are given a name by the World Health Organization [WHO], an international non-proprietary name [INN] … These names started in 1988 with OKT3, which was called muromonab-CD3,” Hale said.
“Then that nomenclature expanded over the next 15 years to include different suffixes to do with the source of the antibody. …But in 2017, these suffixes were abandoned because people started to realize there were so many different ways emerging of engineering antibodies.”
Hale remarked that the sheer number of antibodies being developed today is making it difficult to come up with unique names. To map antibody R&D activity, Hale and his colleagues looked at the sequences of as many products and candidates as they could using artificial intelligence to extract data from the WHO’s INN list.
“So it took an immense amount of curating and looking to decipher all of the sequences from all of the hundreds and hundreds of antibodies, which have entered the clinic,” he said.” And when we put it all together, we ended up with a final data set, which had 819 sequences of antibodies, antibody fusion proteins, and Fc-fusion proteins.”
Diversity
The database, which was published last September, provided significant insights into the type of R&D going on in the sector, according to Hale.
“We were pretty amazed to find that there’s a huge number of formats of antibodies. So, for example, these are the mono-specific antibodies; we found 14 different ways of making antibodies just against one target,” he said.
“But when you get to the multi-specific antibodies, the bispecific antibodies, ’there’s 25 of those in the clinic. And of course, ’there’s many others in development as well.
“And then there’s a great variety of FC fusion proteins where the immunoglobulin FC region has been fused to some other protein to give it a useful property, like half-life. And then there are antibody fusion proteins where the immunoglobulin variable region has been fused with some other protein to give it some new effects or function.”
Antibody Engineering
The analysis also identified candidates that Hale and his colleagues struggled to categorize, as they were so different from other products in development.
“One of them is just an isolated Fc domain, and the others are small molecules conjugated to Fc domains to give them long half-lives,” Hale said.
One less surprising discovery was finding that the majority of antibodies in development are IgG1 type.
“We looked at the IMG globulin subtype, and we found that the most prevalent type of antibody is IgG1. People have been using that for many years when they wanted effective functions to be able to kill cells, say, if you are treating cancer,” he said.
There have been six different allo-types of IgG1 used in the clinical settings, and it doesn’t seem to make a lot of difference which one you use, according to Hale.
“The next most common one is IgG4, and that is being selected when people didn’t want an effector function, they just wanted to neutralise something. And that’s followed by IgG2 and a few others,” he said.
The analysis also underlined the role antibody design plays in development efforts, according to Hale, citing Fc enhancement, half-life extension – where FcRn binding is altered – and Fc silencing as examples.
He also acknowledged the contributions of engineering in the development of antibody drug conjugates, explaining “these are where the Fc domain has been specifically modified to a low site-specific modification with the drug.”
The Future
How such advances will shape the sector in the future remains to be seen. However, the engine driving antibody R&D is the same as the ones that drove “magic bullet” pioneer Paul Ehrlich a century ago, according to Hale.
“Whatever we’re doing in the future, I think the words of Ehrlich will guide us because we still need the very same things he said we needed in order to make successful drugs.
“He called them his four Gs, [which in English are] money. And we know that you need lots and lots of money to fund multiple experiments,” Hale said.
“Then we are going to need lots of patients if we’re going to screen hundreds of antibody constructs. We’re going to need a great deal of skill. And finally, what we’re going to need is luck to find anything successful.”
