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Research & Development
Feature Story
Banking on a Big Biobetters Bonanza
Will China Use its Capabilities to Create Improved Biologics?
By Sabine Louët
Much has been written about biosimilars, due to their ubiquitous and long-standing presence
on the Chinese market. The ability of Chinese firms to engineer their own processes to produce
copies of already authorized biological medicinal product continues to improve. As Chinese
scientists continue to gain experience in biosimilars development, there is a growing interest, if not
expectation, that they will be able to engineer significantly improved biopharmaceutical products
that are aimed at similar targets and carry similar indications to existing biologics products, i.e. to
create biobetters.
The difference between biosimilars and biobetters is sometimes a thin line drawn on the sand
of regulatory landscape, reflecting a difference in the improvement levels. One key distinction,
however, is that biobetters come with the intellectual property protection that may cover differentiating characteristics. Improvement can be due to a new production process, structural modification such as PEGylation, or clinical differences, such as longer half-life in the body, among others.
Such development strategies can also be applied to create entirely novel biologics to tackle a
broad range of diseases, instead of simply improving existing drugs.
In China, there are already existing candidates for the next generation biologics, including
molecules for which there may already be improved analogs. In addition, many of the first generation monoclonals antibodies (mAbs) have already reached or will reach patent expiration within
the next few years, including TNF alpha inhibitors (e.g. etanercept, adalimumab, infliximab), EGFR
inhibitors (e.g. cetuximab), VEGF inhibitors (e.g. bevacizumab), CD20 binder (e.g. rituximab), and
inhibitors of cancer growth controlled by HER2 (e.g. trastuzumab).
So could China jump on the innovation bandwagon and develop its home grown biobetters and
novel biologics? What will be required for a biobetters revolution in China? A few local success
stories could be required to lead the way.
48
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Feature Story
Greater safety
A significant part of the research dedicated to improving biologics focuses on attenuating
immunogenicity to enhance safety.1 Indeed, the principal drawback of biologics has always been
the inherent risk of triggering the body’s immune response. Solutions have already been found.
For example, second generation biologics such as PEGIntron, which constituted an improved
version of erythropeitin, display a better immunogenicity profile. This is thanks to a process called
PEGylation; this involves attaching polyethylene glycol (PEG) polymer chains to the original erythropoietin molecule. PEGylation thus masks the therapeutic agent to the body’s defense, and it is
no longer seen by the immune system as a target. In China, PEGylation has been widely adopted
by research in a wide variety of applications (See Table 1). One of the downside of PEGylation,
however, is that it decreases activity and affinity.
Another safety related issue pertains to the nature of the molecular structure of the drug. Because
some biologics are produced in Chinese Hamster Ovaries (CHO), they feature animal glycosylation finish— where sugar structures are attached to a protein by the production cell lines.
However, animal glycosylation patterns differ from those of human glycosylation. This means that
there is a risk than non-human glycosylation may be less well tolerated by the body, a fact which
has led scientists to attempt to humanize glycosylation patterns in biologic drugs. For example,
researchers at the Center of Molecular Immunology, in Havana, Cuba created a humanized
antibody version of cetuximab (Erbitux), called nimotuzumab2 (BIOMAb EGFR). It was subsequently developed in collaboration with YM Biosciences in Canada, and commercialised, among
others, by Biotech Pharma in China, Biocon in India, and Oncoscience in Europe. Many others
have developed technologies to humanize biologics, including the German glycooptimization
platform company Glycotope, who is developing TrastuzuMab-GEX, an improved version of the
marketed blockbuster drug trastuzumab (Herceptin) (See Table 2).
Table 1: Selected Efforts to Improve Biologics in China
Laboratory
Details
Disease area
Department of Immunology, College of
Preclinical and Forensic Medicine, Sichuan
University , Chengdu
Study of α-momorcharin (α-MMC)—a type I ribosome-inactivating protein (RIP)
from Momordica charantia that is well known for its antitumor and antivirus activities—modified with polyethylene glycol (PEG), and analysis of the toxicity of the
PEGylated α-MMC conjugates (α-MMC-PEG) in vivo 3
Reducing the immunogenicity, immunotoxicity,
and hepatotoxicity
through PEGylation
Enhancing the safety
profile and activity
through PEGylation
Improvement of both
pharmacokinetics and
pharmacodynamics
Department of Medicine, The University of
Study of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced
Hong Kong, Queen Mary Hospital, Pokfulam,
Hepatocellular carcinoma (HCC) patients4
Hong Kong
Use of Human serum albumin (HSA) fusion (Albufusion) technology of
Department of Microorganism Engineering,
interferon-α2b (IFN-α2b) through this study introduces protease cleavage sites or
Beijing Institute of Biotechnology
disulfide linkage between HAS and IFN-α2b5
Study the pharmacokinetics of rhG-CSF, PEG-rhG-CSF and rHSA-hG-CSF in mice
College of Pharmaceutical Sciences,
and to confirm that PEGlyation and albumin fusion of rhG-CSF technology can
Zhejiang University, Hangzhou
prolong half-life of G-CSF6
Creation jof a N-terminal site-specific PEGylated rhG-CSF with higher PEG MolecNational Key Laboratory of Biochemical
ular weight (PEG30 kDa) llonger in vivo circulation half-life and 60% higher drug
Engineering, Institute of Process
bioavailability than mono-PEG20-GCSF7
Engineering, CAS, Beijing
Key Laboratory of Transplant Engineering
Construction ofa recombinant plasmid pCI-HLE encoding human serum albumand Immunology, West China Hospital,
EPO (HSA-EPO) fusion protein and expression in CHO cell 8
Sichuan University, Chengdu
Creation of an artificial gelatin-like protein (GLK) and fused this hydrophilic GLK
Department of Cell Biology, Zhejiang Univerpolymer to granulocyte-colony-stimulating factor (G-CSF) to generate a chimeric
sity, Hangzhou
GLK/G-CSF fusion protein9
Prolonging the half-life of
G-CSF
Increased half-life and
bioavailability
Increased serum
half-life
Extended plasma
half-life
Novel biologic for autoimmune disorders treatment, with improved
efficacy thanks to fusion
technology
Development of a trivalent anti-ErbB2/anti-CD16 bispecific antibody with optimized Improvement of the
structure and minimized toxicity, capable of binding to ErbB2 extracellular domain specificity and affinity
on SKBR3 cells and effectively direct the cytotoxic activities of effector cells to
antibody for breast
SKBR3 cells even at a low concentration11
cancer treatment
Constructed a vector for the expression of a novel compact antibody composed
Jiangsu Province Key Laboratory for
of anti- B-cell-activating factor of the tumor necrosis factor family (BAFF) singleMolecular and Medical Biotechnology, Life
chain antibody fragment (scFv) and the Fc region (the hinge region, CH2, and CH3
Sciences College, Nanjing Normal University
domains) of human IgG1 in Chinese hamster ovary cells10
Institute of Basic Medical Sciences, Beijing
Source: PubMed
© 2012 GB Group Limited. All Rights Reserved.
1. Drug Discov Today. 2011 Apr;16(7-8):345-53. Epub 2011 Feb 12.
2. Zhonghua Zhong Liu Za Zhi.2011 Aug;33(8):626-8 and ZhonghuaZhong Liu ZaZhi. 2011 Mar;33(3):232-5.
3. Immunopharmacol Immunotoxicol. 2012 Mar 23. [Epub ahead of print]
4. Invest New Drugs. 2012 Mar 17. [Epub ahead of print]
5. Mol Pharm. 2012 Mar 5;9(3):664-70. Epub 2012 Feb 1.
6. Yao Xue Xue Bao. 2007 Feb;42(2):197-200.
8. J Biotechnol. 2009 Jul 15;142(3-4):259-66. Epub 2009 Jun 2.
7. Sichuan Da Xue Xue Bao Yi Xue Ban. 2011 May;42(3):317-21.
9. Eur J Pharm Biopharm. 2010 Mar;74(3):435-41. Epub 2009 Dec 6.
10. Appl Biochem Biotechnol. 2009 Jun;157(3):562-74. Epub 2008 Dec 20.
11. Cancer Biol Ther. 2008 Nov;7(11):1744-50. Epub 2008 Nov 4
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Improving the efficacy profile – Increasing half-life
Relying on polymers
Some improvement designed to improve safety, also have a positive effect on efficacy. For
example, PEGylated biologics have a prolonged circulatory time because of their bigger
size, which reduces their filtration by the kidney. Scientists from the National Key Laboratory of
Biochemical Engineering at the Institute of Process Engineering, Chinese Academy of Sciences in
Beijing, have developed an N-terminal site-specific PEGylated recombinant humangranulocytecolony stimulating factor (rhG-CSF). It has a higher molecular weight (PEG 30 kDA) compared to
the existing lighter PEGylated G-CSF (mono-PEG20-GCSF), which is indicated for neutropenia.12
The scientists showed that their improved version had longer in vivo circulation half-life and 60%
higher drug bioavailability than the comparator. This warrants a lower dosage, and therefore lower
cost, while retaining the same therapeutic efficacy.
Other means of extending half-life have been tested, such as the combination of existing
monoclonal antibody bevacizumab (Avastin) with a thermosensitive biodegradable and biocompatible hydrogel.13 This is the approach adopted by a Taiwanese team from the Industrial
Technology Research Institute in Hsinchu, which improved the sustained release of bevacizumab
by packing it into a biocompatible material, composed of a triple block polymer called PEOz-PCLPEOz.
Glycosylation
More strategies to improve the half-life of therapeutic molecules have been developed in parallel.
One approach that has been widely adopted consists in optimization of glycosylation. Additional
glycosylation increases the molecular weight and charge of the molecule and thus reduces the filtration by the kidneys. The challenge is that glycosylation occurs after the gene has been translated,
in what is known as post-translational modification. This matters because the added sugars, or
glycans, serve a variety of structural and, more importantly, functional roles that impact the biological
and clinical properties of proteins. The consequences of changing glycosylation patterns include
changes to activity, half-life time and immunogenicity.14 For example, studies on recombinant follicle
stimulating hormone (rFSH) have shown that increasing the number of N- or O-linked sugar moieties
extends half-life by as much as 100% compared with wild-type rFSH.15
It is nevertheless possible to expand the level of glycosylation further by using an approach referred
to as fusion technology. This consists of creating a hybrid based on modifying the Fc region of
an antibody by adding a subunit susceptible to further glycosylation as compared to the original
molecule. Scientists have, for instance, added a linkage of carboxyl-terminal peptide (CTP) to
enhance glycosylation. This technique has been tested by adding the CTP of the human chorionic
gonadotropin(hCG) beta-subunit, which bears four O-linked sugar binding sites, to recombinant
hormones such as FSH. Such avenues of research have led Merck to the development of corifollitropinalfa (Elonva), which shows sustained follicle-stimulating activity and enhanced in vivo bioactivity
when used as a co-treatment for in vitro fertilization. This approach has also led to the development
of long-acting agents derived from erythropoietin for applications in cancer.16, 17
Improving therapeutic effect – enhancing potency and
selectivity
Fusion technology
Fusion technology has not only been used to enhance safety and the length of molecular half-life
but also therapeutic efficacy. In some cases, increasing the half-life itself has unwanted consequences on the performance of other activity factors. For example, relying on Human serum albumin
50
12. J Biotechnol.2009 Jul 15;142(3-4):259-66. Epub 2009 Jun 2.
13. Biomacromolecules. 2012 Jan 9;13(1):40-8. Epub 2011 Dec 22.
14. Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition.
Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009.
15. Hum Reprod Update. 2009 May-Jun;15(3):309-21. Epub 2009 Jan 30.
16. Endocrinology 2007;148:5081–5087
17. Int J Cell Biol. 2011;2011:275063. Epub 2011 Aug 21.
© 2012 GB Group Limited. All Rights Reserved.
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Research & Development
Feature Story
(HSA) fusion, known as Albufusion, to augment the half-life of a therapeutic molecule, improves the
pharmacokinetics (PK) at the cost of pharmacodynamics (PD), due to the hindrance effect of HSA.
A team from the Beijing Institute of Biotechnology has attempted to bypass this issue by inserting
protease cleavage sites or disulfide linkages between HSA and IFN-α2b.18 They found that fusion
proteins with intermediate release rates had the most balanced PK and PD. In particular, they
showed that this translated into improved therapeutic efficacy in the HT29 human colon cancer
xenograft model.
Further efficacy improvement stemming from fusion technology could come from finding an alternative target to decrease known-side effects. The anti-HER2 antibody Herceptin, for example, is known
to cause cardiotoxicity in patients; also, a high fraction of breast cancer patients show resistance
to the drug. A Portuguese biotechnology company, Biotecnol, developed an anti-HER2 antibody
called Erbicin,19 initially as a fusion of a single-chain antibody fragment (scFv) against human HER2
and the Fc region of a human antibody Immunoglobulin G (IgG). The product was then engineered
as a full IgG antibody. Another aspect of Erbicin is that it binds to a novel epitope located in a region
of the extracellular domain I of HER2 receptor. The company showed in preclinical studies that it
mitigates anti-HER2-associated cardiotoxicity and resistance.20, 21 In a variation of this approach,
scientists in Beijing have developed a trivalent anti-ErbB2/anti-CD16 bispecific antibody with
optimized structure and minimized toxicity, capable of binding to ErbB2 extracellular domain on
SKBR3 cells and effectively direct the cytotoxic activities of effect or cells to SKBR3 cells even at a
low concentration.22
Thinking outside the box to decrease dosing
Enhancing efficacy sometimes means increasing the potency of the drug in order to lower the
required dose of therapeutic product. This could contribute to lowered drug price as due to the
high-cost of bioprocessing.
One strategy to decrease the effective dose of therapeutic molecules consists of improving
the affinity of the therapeutic molecule to the target receptor to increase potency and decrease
off-target effects- an approach that has led U.S. company Trophogen to develop superagonists to
the VEGF receptor, in order to complement bevacizumab (Avastin). They also developed a superagonist to the FSH receptor with three distinct improvements: 1) increasing the affinity of the drug
to the FSH receptor, 2) extending the half-life, and 3) improving the rate of absorption.
Another approach adopted in immune diseases aims at blocking the immune response by
targeting the agents instrumental in triggering the body’s response instead of targeting their
receptor, such as cytokineinterleukin-6 (IL-6). There are cost advantages to this approach as
far less antibody is required to block IL-6 itself versus its receptor. This is the strategy adopted
by Femta Pharmaceuticals of San Diego, California with its candidate Fm101 for the treatment of
rheumatoid arthritis (RA), Crohn’s disease and myeloma.
Awaited shift in biologics market leaders
The Chinese government actively supports biobetters development. Introduced in November
2011, the “Biotechnology Development Plan” funded under the 12th Five-Year Plan (2011-2015)
has earmarked RMB 20 billion for new drug development and control of disease. It also supports
the development of new technology for large-scale antibody development. In addition, it prioritizes
the the building and optimization of humanized antibodies through bio-engineering and biomanufacturing.23
© 2012 GB Group Limited. All Rights Reserved.
18. Mol Pharm. 2012 Mar 5;9(3):664-70. Epub 2012 Feb 1.
19. FEBS Journal 278 (2011) 1156–1166
20. Br J Cancer. 2010 Feb 2;102(3):513-9. Epub 2010 Jan 5.
21. FASEB J. 2009 Sep;23(9):3171-8. Epub 2009 May 5.
22. Cancer BiolTher. 2008 Nov;7(11):1744-50. Epub 2008 Nov 4.
23. http://www.most.gov.cn/tztg/201112/t20111209_91321.htm
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Chinese capabilities in providing cost-effective support for engineering and developing novel
biologics are increasingly recognised by the international biologics community. In fact, Femta
relied on antibody engineering platform company BioAtla to develop their products, including
Fm101. With operations in San Diego and Beijing, BioAtla has also supported other U.S. biobetters
companies such as San Diego-based VivaMab.
The number of Chinese bioengineering development companies, including those with their own
innovative products, also continue to rise (See Table 2). To name only a few, Genor Biopharma
(Shanghai), Innovent Biologics (Suzhou), Simcere Pharmaceutical Group (Nanjing), and PacificMeinuoke Bio-pharma (Changzhou) are among them. These companies often have their own
GMP biomanufacturing facilities which are actively supported by the Ministry of Science and
Technology under the 12th Five-Year Plan 2011-2015. Such extended capabilities have spurred
these companies to collaborate with both domestic and international partners for the development
of proprietary biologics.
The realm of possibilities to produce biobetters and novel biologics is vast. There are many strategies available to improve both safety and efficacy in order to decrease the dose required for treatment, and ultimately decrease the cost of improved biologics drugs. There is a clear opportunity
for Chinese players to be part of the next biologic evolution, given the know-how and the expertise
present in the country. Companies offering improved biologics may have a chance to become
tomorrow’s market leaders. Chinese companies, who are already on the starting blocks, will be
part of this challenge and will stand a good chance in the race to global markets.
Table 2: Selected worldwide R&D efforts to create next generation novel biological drugs
Product (Company)
Details
Gensci 004 (GeneScience
PEGylated human growth hormone
Pharmaceuticals, China)
MB 03002 (LG Life Science, South
Slow release hGH based on biodegradable matrix24
Korea/ Biopartners, Switzerland)
Progress
Indication
Phase 3
completed
Growth delay
Phase 3
Growth delay
Nimotuzumab (BIOMAb EGFR)
(Center of Molecular Immunology,
Cuba/ YM Biosciences, Canada)
First humanized version of anti-EGFR monoclonal antibody
cetuximab (Erbitux), designed to reduce adverse events
Phase 2 and 3
clinical trials for
different indications
Lung cancer (NSCLC)
and brain tumor (glioma),
among others
hyFc EPO
(Genexine, South Korea)
Antibody fusion protein technology, called Hybrid Fc(hyFc) technology,
applied to erythropoietin to increase its half-life
Phase 1
Anemia, Neutropenia
Uricase-PEG 20 (3SBIO, China)
PEGylated recombinant uricase derived from Candida utilis
Phase 1
Refractory gout and tumorlysis syndrome
Follicle-Stimulating Hormone whose glycolisation has been
humanized using the company’s GlycoExpress technology
Phase 2
Fertility treatment
Phase 1
Diabetes
Phase 1
Hodgkin’s Lymphoma
IND
Non-Small Cell Lung
Cancer
IND
Rheumatoid arthritis
Preclinical
Rheumatoid Arthritis
FSH-GEX (GT-GP 2.4-GEX™)
(Glycotope Biotechnology,
Germany)
Insulin analog (Bioton, Poland)
XmAb® 2513 (Xencor, USA)
PEGylatedEndostar(Simcere
Pharmaceutical Group, China)
Fm101
(Femta Pharmaceuticals, USA )
SSS07 (3SBio, China)
Human insulin analogue with extended half-life
Humanized monoclonal antibody that targets the antigen CD30,
engineered to contain an mAb Fc domain to greatly increase its cytotoxic
potency
PEGYlated version of the first recombinant human endostatin, an innovative
anti-angiogenic drug that was first approved by SFDA in 200525
A monoclonal antibody that blocks the interleukin-6 (IL-6) protein instead
of inhibiting the IL-6 receptor
Genetically engineered anti-TNF humanized monoclonal antibody with
enhanced affinity (entanercept/infliximab/ adalimumab competitors)
IBI 301
(Innovent Biologics, China)
Humanized monoclonal antibody against CD20, which is an improvement
Preclinical
over the chimeric CD20 antagonist rituximab
HiPEG IFN α-2a
(PolyTherics Ltd, UK)
An improved interferon alpha-2a based on PEGylation technology
enabling site-specific PEGylation of any protein or peptide
A fully human anti-HER2 antibody fragment with high affinity and selectivity for ErbB2-positive cancer cells, targeting a novel epitope compared
to trastuzumab
A monoclonoal antibody engineered for higher affinity, and surface
binding to its target to enhance potency that is conjugated with a linker to
improve the delivery of of cytotoxic component
Triple biobetter based on super active analogs of FSH hormones with
improved affinity, extended half-life and increased rate of absorption
Erbicin, (Biotecnol, Portugal)
VM 101
(VivaMab, USA)
FSH superagonist
(Trophogen, USA)
Non-Hodgkin
Lymphoma,Chronic
Lymphocytic Leukemia
and rheumatoid arthritis.
Preclinical
Hepatitis
Preclinical
Breast cancer
Preclinical
Haematological cancer
Preclinical
Fertility treatment
Source: company web sites, clinicaltrials.gov, GBI SOURCE
52
24. J ClinEndocrinolMetab. 2012 Feb;97(2):400-7. Epub 2011 Dec 7 and linEndocrinol (Oxf).
2012 Jan;76(1):88-95. doi: 10.1111/j.1365-2265.2011.04146.x.
25. Int J BiolMacromol. 2010 Apr 1;46(3):331-6. Epub 2010 Feb 1.
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