With the goal of expanding access to
antibody-based drugs worldwide, the Bill & Melinda Gates Foundation is
turning to industry to innovate its methods of manufacturing the proteins. In the
last two months, the organization signed deals with Biogen Inc. and Just
Biotherapeutics Inc., fostering programs to reduce costs and increase yields
that benefit both the for-profit and not-for-profit enterprises.
On Aug. 8, the Gates Foundation and Biogen
announced a project to improve antibody production and manufacturing
techniques, using eight undisclosed expression systems that include yeast,
fungi and algae. The idea is to search for alternatives to Chinese hamster
ovary (CHO) cells, which have served as the workhorse of antibody manufacturing
for 25 years. Biogen will conduct the research over an 18-month period, and the
results will be made publicly available.
Financial details were not disclosed but the
organizations are contributing roughly equal amounts, according to Stephen
Hadley, senior program officer for vaccine development at the Gates Foundation.
Hadley said Biogen is also contributing an antibody to use as a benchmark and
some of the analytics.
The partnership comes two weeks after the
Gates Foundation invested $8 million in a series A2 round for Just
Biotherapeutics, a start-up focused on streamlining antibody production. A
further $6 million was invested by existing investors Merck & Co. Inc.,
Lilly Asia Ventures and Arch Venture Partners. Last year, the foundation
awarded the company $24 million in grants over five years to develop low-cost
HIV antibodies and technology platforms for low-cost biologics.
Despite the success of CHO cells for
supporting antibody production, the yield has hit a ceiling after years of
optimization; however higher yields and more streamlined manufacturing are
needed to reduce costs for emerging and third world markets.
But according to Tim Moore, EVP of technical
operations at Kite Pharma Inc., since the 1990s when a platform based on CHO
cells was established, there has been little motivation in industry to innovate
or switch expression systems. Moore was previously SVP and global head of
Pharmaceutical Technical Operations Biologics at Roche’s Genentech Inc. unit.
“There were hardly any players in that space,
so it made a lot of sense just to build upon [the early methods] and then come
up with different ways to get higher titers,” he said.
Hadley told BioCentury that was the first
challenge he faced when he joined the organization three years ago and was
tasked with exploring mAbs for infectious diseases at production costs that
could be practical in focus regions such as sub-Saharan Africa and South Asia.
“Most of the antibodies and biologics developed
for the world marketplace enjoy extremely nice margins, so for cost of goods
there has never been a pressure driver on the industry to figure out how to
lower costs,” he said.
Hadley said there was little interest among
most of the biotechs he spoke to about developing better methods. “Frankly,
people are pretty set with their processes and installed capacity.”
However, the Gates Foundation’s approach was
to make “catalytic investments” that will get the field to move in a new
direction, said Hadley, and to find industry partners that see a commercial
benefit to improving the technology that complements rather than competes with
the organization’s interests. “We don’t have any alignments on products; this
is all around technology. Their portfolio of products is different than our
interests.”
Whereas the funding for Just Biotherapeutics
supports lower-cost methodology for CHO-based manufacturing, the Biogen project
is looking beyond CHO cells, and is using an open model that hopes to engage
other companies that might see the upside of creating a next-generation,
low-cost platform.
Jorg Thommes, SVP of technical development at
Biogen, told BioCentury the field has reached an inflection point. “We’re now
at this point of saying ‘OK what’s next?’ Will it be mammalian cells forever?
Or is there an opportunity to get even better and to get to the next step
change in productivity?” he said.
WHOLESALE
CHANGES
According to Thommes, the ongoing adherence to
CHO cells has not been for want of trying to find alternatives. The problem has
been that there’s been no coherent or coordinated strategy to replace the
cells.
“People have been trying out alternate
expression systems for a long time,” he said. “And they’ve been executed
sporadically with different focus. And there has never been a real head to-head
comparison of many alternate expression systems with the current
high-productivity mammalian cells.”
Overall, the efficiency of antibody production
from CHO cells has increased by a factor of nearly a thousand in the last 25
years, with common yields approaching 3-6 grams per liter of CHO cells, due
largely to a greater understanding of CHO cell biology, said Thommes. “We’ve
gotten much, much better at understanding what these cells need to grow and thrive,
so we can maximize their number in a reaction system and the time that we can
keep them alive and happy.”
But those improvements also capped progress.
“Mammalian cells make proteins that are very well tolerated by humans and are
fully functional. So, there was no need to look outside of that mammalian cell
box because we got so much better at it,” Thommes said.
However, the main drawback is the long growth
cycle, he said. Mammalian cells are typically cultured for 10-14 days during a
production run, compared with 2-3 days for yeast or bacteria. Microbes are used
at large scale to produce biologics like insulin and human growth hormone,
which are made in yeast and bacteria, respectively
Thommes said that the main advances have been
in the “upstream” part of antibody manufacturing, which involves protein
production, where using lower-cost media and achieving higher titers has
improved productivity and reduced costs. But the principal need is in the
“downstream” part of the process which involves protein purification, where
costs have remained stagnant.
“Alternate expression systems with increased
productivity will most likely present a different, possibly leaner, background
to isolate antibodies from. This could open up intriguing opportunities for
disruptive downstream processing technologies,” said Thommes. In particular, he
thinks replacing traditional chromatography methods with other unit operations
might be interesting, and the current focus on virus inactivation and removal
steps for mammalian cell expression might be reduced with alternate hosts.
Hadley believes that the results of the Biogen
project can seed bigger advances once opened up to the research community. “I
think the trajectory would be similar to what happened with CHO. Eventually
organizations, when they landed on CHO, they brought their own CHO cell lines
and vector technologies into their own organizations, optimized them, and
controlled the IP around that.”
JUST SAYIN’
By contrast, the investment in Just
Biotherapeutics is meant to help the start-up double down on CHO cells, using
protein engineering and infrastructure improvements to reduce costs. “It’s the
extreme opposite of the very large-scale stainless-steel model that’s been very
successful, but there’s a production cost floor that it’s difficult to figure
out how to break through,” said Hadley
The company was started by a team of Amgen
Inc. veterans, who aim to introduce changes throughout the process, from
molecule design to facility layout, to lower costs tenfold and bring cheaper
antibodies to developing markets.
“You have to look at it holistically. You have
to look everything from molecular design for manufacturability all the way
through the plant and how well the plant is designed. So, we can optimize in
both directions,” said Just CEO Jim Thomas.
Hadley said the Gates Foundation is solely
interested in infectious disease antibodies in the project, which it wants to expand
to third world nations, following the model of Synagis palivizumab, a humanized
mAb against respiratory syncytial virus (RSV) from AstraZeneca plc’s MedImmune
LLC unit.
For the HIV project, the target product
profile calls for a subcutaneous product dosed quarterly. The aim is to use
protein engineering to enable low-viscosity formulations at about 150 mg/mL,
and modifications to the Fc region to extend the half-life.
Hadley said the Gates Foundation grant covers
HIV antibodies from four different academic groups funded by the Collaboration
for AIDS Vaccine Discovery (CAVD). The antibodies include eCD4-Ig from The
Scripps Research Institute and 3BNC117 and 10-1074, which are in Phase I
trials, from The Rockefeller University.