European Biotechnology News Special 3/2012 - Antibodies & Markets

European Biotechnology News Science & Industry

March 2012

II Antibodies 2.0 – unlocking new markets

SPECIAL 29_EBSIN3-12_Special_Titel_tg.indd 1

02.03.2012 14:27:17 Uhr

European Biotechnology Net work

builDing transatlantic PartnershiPs in biotechnology 30 th March | Brussels Join the European Biotechnology Network to explore how European biotechnology research can build US partnerships through the key funding mechanisms open on both sides of the Atlantic. Framework Programme Seven and Horizon 2020 from Europe combine with National Institutes of Health (NIH), Department of Defense (DOD) and the Bill and Melinda Gates Foundation from the US. Academia and industry from the US and Europe can fund partnerships through these programmes and accelerate technology and clinical/market application. The day brings together the European Commission and organisations active in EuropeanUS partnerships, from academia, SMEs and pharma, to showcase partnerships and the mechanisms behind them.

ss !

Doing the busine 2 9th March 2 012

ted by ‘Doing the busiPar tnerships is suppor Building Transatlantic istics of biotechnology log the workshop on ness’, an intensive 1 day le, the day focuses h just 15 places availab business in the US. Wit corporate par tners, ces suc for with factors beyond the technology, tion into different nts and effective integra ing, investment and gra ture. market and biotech cul click on our events iotechnology.net and Visit www.european-b k your place! to find out more and boo

In the memory of last year’s inspirational keynote speaker, Ian Bathurst, the meeting supports Medicines for Malaria Venture (MMV) a Swiss-based publicprivate initiative whose donor, stakeholder and grantee network across the US and Europe is exemplary of the kind of partnership we hope toshowcase.

Please register now at www.european-biotechnology.net through the event pages.

Meeting supported by:

Grünecker Patent- und Rechtsanwälte

European Biotechnology Foundation | Rue d’Egmont 15 | B-1000 Bruxelles, Belgique Tel: +32 2 50 08 531 | Fax +32 2 64 92 989 | info@european-biotechnology.org | www.european-biotechnology.net

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Nº 3 | Volume 11 | 2012

Euro|Biotech|News

31

Special: aNtibodieS & MarketS Intro

Biotech partnering and the other IP Intellectual Property (IP) is without question one of the most vital aspects of any bio­ tech venture, a key and undisputed factor for success. However, most biotech com­ panies are still incapable of unlocking the value of their intellectual property all on their own. they need another kind of IP – Intelligent Partnerships, especially in the expanding monoclonal antibodies market.

Since the beginning of the economic crisis, the biotechnology sector has had to endure a lot of negative news, even suggestions that the industry as a whole could collapse. Whilst overly exaggerated, the current viewpoint is certainly grave. But let’s look at the abbreviation of IP in another way: Intelligent Partnerships! Below are a couple of examples of this essential area that we consider important to the future of the biotech industry.

IP between academia and industry is key to the sustainability of the sector.

The raw material for new start-up ventures is mostly a transfer from universities into industries. Understanding how to manage the interactions between the public partner (which most universities are) and the private sector is an indispensable ability for future development of the company. Evaluating science amongst peers becomes more important as the industry grows more global.

ip requires smart money!

IP often requires good, experienced and well-connected investors. Only if smart money finds its way into the venture can you expect solid development of results and milestone achievements. The prudent investor base isn’t only involved in the Life Science and Biotechnology sectors. If investors see better (or safer) future exits for their money, they will turn

31_EBSIN3_12_Special_Alexakis_tg.indd 31

the author: Domenico Alexakis is the founding partner of Bridge Plus AG based in Zurich, Switzerland. His company manages various projects and initiatives for the stakeholder community of Life Sciences and Economic Development. He also serves as CEo of the Swiss Biotech Association (SBA).

away from our risky but highly-rewarding industry and invest in other areas.

IP is also necessary with a view to fostering increased respect for the research community. Its members produce innovation, which leads to new products, new cures, new production methods, new companies and to more jobs. The service sector depends a lot on a pipeline of new ideas that can be turned into products with commercial value. In the past, society respected researchers and engi-

neers much more than they do today. We should alter that current perception as quickly as possible and motivate young talents to look for professional success in science and engineering.

IP works well in countries where major government and industry funding is available. These entities invest and manage start-up funds, and by doing so create a pipeline of new companies. Critics might say that too much state aid is not good for the sector, but managed well, rewards are higher than initial investments. After all, a larger and improved work force is the goal of any economy.

ip needs cluster management Not many industries are better equipped to be grouped into clusters based on Porter’s theory of building competitive advantages. Hotbeds of biotech can be found in countries all over the world, and they compete with one another. If that competitive spirit leads to better science and economic output it’s all well and good, but if it becomes an obstacle for sustainable development then it’s better to change strategies. The size of a country also determines the number of clusters.

Related to the IP of cluster management is the fact that transatlantic collaborations in the public sector need to be improved. For decades, academic institutions have worked with peers all over the world, but funding agencies still hold off on investments. The European Union’s FP-programmes are steps in the right direction, but the bureaucracy for each programme remains high.

Partnering events like the BIO-Europe Spring are also good platforms for starting sustainable relationships.

Stimulate ip!

Last but not least, IP in creating an improved and better image for biotechnology is a must. Biotech is a far-reaching instrument for providing good solutions to the world’s most pressing issues, but we all need to use its tools wisely and have patience. Intelligent Partnerships can only grow if we are all taking part. B

29.02.2012 17:43:54 Uhr

32

Nº 3 | Volume 11 | 2012

Euro|Biotech|News

Special: aNtibodieS & MarketS BIO-EUROPE SPRING

Dealmaking in 2012 off to a good start European dealmaking numbers went up in 2011, but what will 2012 look like? It’s still early days, but the year has already seen some major agreements and takeovers. With the exception of Roche, which has issued a US$5.7bn hostile bid for Illumina Inc., most of the activity is dominated by US companies like Amgen, BristolMyers-Squibb and Celgene. Because many antibody patents run out this year, however, the biosimilars sector in particular is expected to see a lot more action.

By 2017, biologics revenues of US$60bn are in danger due to patent expiry, according to an analysis by Burrill & Co. Despite its special requirements, biosimilar development has become a very popular area.

None of the currently approved biosimilars comes even close to antibodies in terms of complexity, but financial incentives make the idea of biosimilar antibodies tempting.

Remicade (US$4bn in annual sales) goes

off-patent in Europe in 2014. Herceptin (US$5.7bn) and Rituxan (US$5.5bn) follow in the same year and 2015, respectively.

One of the most active players in the market is Merck & Co. The US pharma is aiming to have five biosimilars in late-stage testing by 2011. To do so, it has formed various alliances. Merck’s new friends include the CRO Parexel and South Korean manufacturer Hanwha Chemical. The partners are currently trying to bring to market a generic version of the fusion protein Enbrel (sales of US$6.2bn in 2010). And there are new players in the sector, including Samsung. The South Korean electronics conglomerate known for mobile phones and flat-screen TVs has identified biologics as a promising target. Over the next 10 years, it’s investing US$1.9bn in the area. Even Amgen, not long ago one of the strongest opponents of biosimilars, has teamed up with Watson Pharmaceuticals to develop and commercialise biosimilar oncology drugs, among them many antibodies.

D

European dealmaking in 2010 – 2011 M&A Deal Volume

2010

2011

Change

20,864

50,324

141%

54

63

17%

386

799

107%

20,864

15,024

-28%

54

61

13%

386

263

-32%

20,497

27,457

34%

INBOUND: EUROPEAN TARGET Total Deal Volume (USD M) Number of deals Average deal value (USD M) If deals >$10bn are not included Number of deals Average deal value (USD M) OUTBOUND: EUROPEAN ACQUIRER (EX-EU ASSETS) Total Deal Volume (USD M) Number of deals Average deal value (USD M) If deals >$10bn are not included Number of deals Average deal value (USD M)

45

32

-29%

455

858

88%

20,497

7,357

-64%

45

31

-31%

455

237

-48%

8,971

9,972

11%

52

50

-4%

173

199

16%

20,725

8,625

-58%

Partnering Total Deal Volume (USD M) Number of deals Average deal value (USD M) OUTBOUND: EUROPEAN LICENSEE (EX-EU ASSETS) Total Deal Volume (USD M) Number of deals Average deal value (USD M)

32_EBSIN3_12_Special-Intro_pad.indd 32

51

31

-39%

406

278

-32%

© modified by BIOCOM from Burril & Co.

INBOUND: EUROPEAN LICENSER

29.02.2012 17:44:39 Uhr

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34

N –º 3 | Volume 11 | 2012

Euro|Biotech|News

Special: antibodieS & MarketS Glymaxx® technoloGy

Enhancing ADCC Dr Hans Henning von Horsten and Dr Volker Sandig, ProBioGen AG, Berlin, Germany

monoclonal antibodies have become a dominant class of therapeutic proteins. Several antibody therapeutics are sold and marketed worldwide, and many more are currently in various stages of clinical development. the discovery and development of these substances – particularly in oncology – is progressing at an ever-increasing pace, and, cancer continues to be by far the most common indication for therapeutic antibodies.

The therapeutic efficacy of an antibody is determined by its pharmacokinetic and pharmacodynamic properties – and Nlinked glycosylation is by far the most deciding factor impacting on both[1-2]. For most oncology indications where a therapeutic antibody directly mediates the killing of tumour cells, the effector functions are of utmost importance for the antibody’s pharmacodynamic efficacy [3-6].

This is also true for another emerging class of therapeutic antibodies – those that are directed towards targets in infectious disease applications[7).

The elimination of fucose from the Nlinked sugar chains on an antibody has long been shown to dramatically en-

hance the antibody-dependent cellular cytotoxicity (ADCC), the most powerful anti-tumour activity mediated by antibodies[8). The ADCC-enhancing effect of missing core-fucose has recently been shown to be additive to the effect of antibodies that have been Fc-protein-engineered for enhanced ADCC[9).

GlymaxX®-modified cells are shown to produce almost 100% fucose-free antibodies. Armed with a powerful ADCC-effector function for tumour annihilation, these fucose-depleted antibodies show an increased binding affinity to the Fc gamma receptor.

The technology is based on the heterologous, cytosolic expression of RMD, an

enzyme that redirects the de-novo fucose synthesis pathway towards a sugarnucleotide that cannot be metabolised by eukaryotic cells. Thereby, the substrate for cellular fucosylation, activated GDPL-fucose, is depleted and fucosylation is almost completely abolished(10).

The activity of the RMD enzyme ensures fucose-depletion largely independent of RMD expression level. This independence directly contributes to a stable level of defucos ylation over an extensive number of cumulative population doublings, and it also compensates efficiently for any possible scale-up related impact on the desired afucosylation level. In combination with state-ofthe-art vector technology, the GlymaxX®modified clones have shown stable transgene expression and function.

The GlymaxX® technology is simple to apply and completely compatible with manufacturing processes in any eukaryotic host cell line, which means that it can be applied to already-existing producer cells regardless of species origin.

GlymaxX® modified cells can be generated and reposited under GMP. Performance parameters of the host cell line – such as doubling time, growth rate, maximum viable cell density and achievable IVCD – remain unaffected by the GlymaxX®-modification, and thus remain identical to those of the parental producer clone.

Taken together, Gly max X ® wor k s seamlessly with the systems and processes our clients and partners already have in place. 

References References can be seen at www.eurobiotechnews.eu in the section Tech Reviews contact Dr Gabriele Schneider VP Business Development ProBioGen AG Goethestr. 54 13086 Berlin, Germany

Figure 1: antibodies produced from Glymaxx®-engineered cells contain a reduced amount of core-fucose, show an increased ability to recruit nK-cells, and mediate an efficient antibody dependent cellular cytotoxicity (aDcc) response.

34_EBSIN3_12_Special_Probiogen_tg.indd 34

Tel.: +49 30 924006-0 cmo@probiogen.de www.probiogen.de

02.03.2012 14:28:12 Uhr

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01.03.201205.10.11 11:36:4616:36 Uhr

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Nº 3 | Volume 11 | 2012

Euro|Biotech|News

Special: aNtibodieS & MarketS Biomanufacturing

the crossMab <ang2/VeGF>

Bispecific antibodies & single-use devices

The bispecific antibody binding both Ang2 and VEGF-A is expected to weaken and ultimately eliminate a tumour by reducing the supply of nutrients from blood vessels, thereby suppressing tumour growth.

Blood vessel formation requires a complex sequence of steps stimulated by Ang2 and VEGF-A. Because they are essential for angiogenesis, inactivating these two growth factors should allow the bispecific antibody for Ang2 and VEGF-A to strike the tumour effectively.

Different challenges had to be addressed when developing the CrossMAb < Ang2/VEGF>. The most important prerequisite was that the four protein chains be expressed in the correct, stable stoichiometric relationship. To do this, two DNA plasmids, each carrying the genetic information of one light and one heavy chain, were transferred into CHO cells. Both plasmids were mixed in different ratios, and the resulting cell clones were analysed. Twelve of the best candidates were subcloned and 23 of these subclones were characterized intensely in shake flasks and 2L bioreactors. The most important parameters for selecting the clones and subclones were IgG quantification and the analysis of unwanted byproducts, such as incomplete antibodies or heterodimers of two light chains. The best clones were further tested for expression stability, product quality, glycosylation pattern, structural integrity, antigen binding and bi-functionality. In order to produce material for preclinical toxicological studies, the selected clone was cultivated in 100L and 250L SUBs. During these fermentation processes, cells reproducibly reached densities of up to 8 x 106 mL-1 and maximal product concentrations of 4g/L-1.

Stefan Koch, Ingo Gorr und Wolfgang Paul: Roche, Biologics Research, Pharma Research and Early Development (pRED), Penzberg

the use of bispecific antibodies recognising two different targets may allow improvement of clinical efficacy. a bispecific antibody for two growth factors that stimulate the formation of blood vessels – ang2 (angiopoietin-2) and VEgf-a (Vascular Endothelial growth factor a) – has been developed by roche Pharma research and Early Development (prED). for the first time, single-use bioreactors (SuBs) in roche’s fermentation plant have been used for production of this bispecific antibody for toxicological studies, successfully combining two emerging technologies.

the SuB plant of roche Pharma research and Early Development in Penzberg

Bispecific antibodies incorporate the antigen -binding properties of two different monospecific antibodies. The basic principle underlying this technology involves transformation of the host cell line with the genetic information encoding for four different protein chains. Although the cell line produces the desired combination, it may also yield nine other antibody combinations. In order to avoid the mispairing of heavy and light chains,

36-37_EBSIN3_12_Special_Roche_tg.indd 36

the protein chains have to be altered in a way that favors the formation of the correct molecule. This is achieved by two pivotal changes: first, the CH3 domains of two heavy chains are modified so that one exhibits a knob and the other a hole. The second alteration ensures the correct pairing of the light chains to their corresponding heavy chains. This is done via the crosswise exchange of CH1 and C in one arm of the antibody to produce a CrossMAb.

design of the SUb plant The conceptual design phase of the SUB plant revealed that cell growth and product yield in different types of SUBs are comparable to those in stainless steel fermenters. The rocker and stirred tank vessels that were ultimately chosen are

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210x8

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Special: aNtibodieS & MarketS combined in such a way that their split ratio is 1:5, and each pre-fermentation line supports two main fermenters. The plant consists of 50 L, 100 L and 250 L fermenter lines (see Figure). Because each reactor has ports for feeding nutrients, all of the pre-fermenters can also function as main fermenters. Flexible tubes connect the different reactors. Depending on the desired combination, split ratios between 1:2 and 1:10 can be realized.

Fermentation systems and processes The cell-culture media are prepared in stainless steel vessels with working volumes of 60-600L for single or multiple fermentations. Finally, the media are passed through sterile filters into storage bags or directly into fermenter bags. The cells are cultivated in 10-20L bags, which are fixed on a rocking system that is aerated through the head space. SUBs with a working volume of 50, 100 und 250L are cylindrical, and contain a marine impeller for mixing the culture. The bag is aerated via submerged gas injection. All fermentation units are mounted on wheels and are supplied with the required media (gases, electricity) from the ceiling, which allows them to move when desired.

Temperature, pH and pO2 are recorded and controlled in every fermentation bag. Some types of bags contain only op-

tical sensors with a disposable sensor patch to measure pH and pO2, while others also allow users to insert electrochemical probes. Additional single-use sensors control pressure in the bags and enable monitoring of foam formation. The pressure control prevents overpressure, which can cause disruption of bags. Online and offline data are recorded and visualised, with different parameters of several fermenters shown in a single plot. This allows it to make fast comparisons, even between ongoing fermentations. 10-50L cultures are harvested using depth filtration or swing-head centrifuges with a capacity of 6-12L. In 100-250L fermentations, the cells are removed by separators.

The reactors support Roche Pharma projects by culturing many cell lines and applying different process techniques, allowing for batch and fed-batch processes with up to three nutrient feeds. To provide proteins for early project phases, mammalian cell lines are transfected with DNA plasmids, or insect cells are infected with baculoviruses. Murine hybridoma lines can also be cultivated in SUBs. During late project phases, stably-expressing CHO lines are used for producing material for preclinical toxicological studies, as is the case with the CrossMAb <Ang2/VEGF>.

Bioprocesses with stable CHO lines are transferred to the GMP area, equipped with identical 250L SUBs and meet the de-

mand for the early clinical phases. Implementing SUB technology at Roche’s site in Penzberg established a fermentation platform producing enough material to cover demand from early project phases up through clinical studies.

outlook The CrossMAb < Ang2/ VEGF > proves that these new antibody formats can be manufactured for therapeutic applications. Further development of these formats will lead to proteins that are designed for specific indications and that clearly differ from naturally occurring antibodies. SUB technology allows it to shorten development timelines and to use identical processes for supply of GLP-tox and early clinical phases. Fermenters on a scale of about 10 m³ are needed for late clinical phases and market supply. Stainless steel reactors will continue to be used for these applications, as these dimensions are still difficult to achieve with SUBs. D Contact Stefan Koch, Ingo Gorr und Wolfgang Paul Roche Diagnostics GmbH, Biologics Research Pharma Research and Early Development (pRED) Stefan Koch@roche.com Please request references under this e-mail and refer to www.eurobiotechnews.eu; “Tech Review” Section.

Life Sciences.

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Nº 3 | Volume 11 | 2012

Euro|Biotech|News

Special: aNtibodieS & MarketS NeurImmuNe

Evolved treatments for Alzheimer’s Jan Grimm (CSO) and Roger Nitsch (President), NeurImmune AG, Zurich

Zurich-based NeurImmune AG follows unconventional routes – for example, the company doesn’t rely on VC investors. And Neurimmune has also turned the drug discovery process upside down by taking its drug candidates from healthy humans that have developed an immune response to pathogenic proteins like Abeta.

Biogen Idec is building on NeurImmune’s expertise, and has already signed two agreements.

The deposition of pathogenic protein aggregates derived from physiological brain proteins is a common theme underlying most neurodegenerative diseases. These protein clusters deposited in the brains of human patients include, for example, Abeta (Ab) and tau in Alzheimer’s disease and Down syndrome, a-synuclein in Parkinson’s disease and dementia with Lewy bodies, and superoxide dismutase 1 in amyotrophic lateral sclerosis. Disease-causing mutations in the genes encoding these proteins point to their central roles in the etiology of neurodegeneration. Both genetic and the more frequent “sporadic” variants of neurodegeneration are associated with the conversion of misfolded physiological proteins into pathogenic aggregates.

prion-like mechanism Synaptic connections by which neuronal networks communicate are among the most vulnerable structures affected, resulting in the progressive deterioration of neuronal network activities. When released from affected cells, the pathogenic aggregates can enter unaffected neighbouring cells, bind to their cognate physiological protein counterparts, and force them to adopt pathological conformations as well. This thermodynamically driven process of prion-like infectiv-

38_EBSIN3_12_Special_Neurimmune_pad.indd 38

NeurImmune’s CNS therapies rely on natural antibodies from healthy volunteers.

ity drives the spatiotemporal spreading of protein aggregation from cell to cell and throughout the central nervous system. Unexpectedly, this metamorphosis from physiologic to pathogenic structural conformations of endogenous proteins can be accompanied by humoral immune responses generating B-cells encoding high-affinity antibodies that specifically bind and neutralise such pathogenic protein aggregates. This observation provides a basis for asking the questions of how healthy elderly subjects succeed in preserving intact cognitive functions during aging, and how such knowledge can be used pharmacologically to prevent neurodegeneration in subjects at risk. NeurImmune studied immune responses directed against pathogenic pro-

tein aggregates in cohorts of healthy elderly subjects with either excellent cognitive performance or recovery from initial signs of cognitive decline. Up to 80% of healthy elderly subjects had established B-cell memory against aggregated Ab, thus allowing for the cloning of human monoclonal antibodies targeting these aggregates. Recombinantly produced human monoclonal antibodies with high affinity and selectivity for aggregated Ab crossed the blood-brain barrier in transgenic mouse models of Alzheimer’s disease and accumulated on Ab deposits in the brain. Brain-resident microglial cells were recruited to antibodylabeled aggregates, and removed them by means of phagocytosis paralleled by signs of neuronal recovery and restored behavioral functions. The pharmacological effects of these human monoclonal antibodies are currently being studied in human patients with early signs of cognitive decline. In addition to immune responses against aggregated Ab, healthy elderly subjects also mounted immune responses against misfolded or aggregated forms of a-synuclein, superoxide dismutase 1, tau and TAR DNA-binding protein 43. The corresponding high affinity human monoclonal antibodies were cloned, sequenced, produced recombinantly and validated in vitro and in vivo. As an example, chronic treatment of transgenic mice with signs of amyotrophic lateral sclerosis established rescue of alpha-motor neurons along with increased overall survival. Likewise, recombinant human antibodies against a-synuclein decreased alpha-synuclein pathology and improved motor functions in transgenic mouse models of Parkinson’s disease.

Pharmacological intervention using recombinant human antibodies against diseasecausing toxic protein aggregates provides a promising concept for the treatment and prevention of neurodegeneration.

In November 2007, Biogen Idec closed a first partnership with NeurImmune for the development of antibodies to treat Alzheimer’s disease. Neurimmune could receive an aggregate of US$380m in up-front and success-based milestone payments. In December 2010, Biogen acquired a NeurImmune subsidiary that contained the global rights to three preclinical candidates targeting neurodegenerative diseases. B

29.02.2012 18:04:18 Uhr

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40

Nº 3 | Volume 11 | 2012

Euro|Biotech|News

Special: aNtibodieS & MarketS process development

Effectively upscaling bioprocesses Claudia M. Huether, DASGIP AG, Jülich, Germany; Patrick Priem and Jolanda Gerritsen, Genmab B.V., Utrecht, the Netherlands

success in the biopharmaceutical industry is mainly driven by the ability to innovate, and the continuous development of new products is crucial in that context. shortening development times is key. the use of comprehensive bioprocessing equipment supports the quick establishment of valid bioprocesses, and facilitates easy and reliable scale-up from lab to production plant. Genmab scientists have demonstrated how powerful methods can accelerate the development of antibody production processes.

Jolanda Gerritsen and her team at Genmab in Utrecht in the Netherlands have used a fourfold DASGIP Parallel Bioreactor Sys­ tem to shorten the development time of an antibody production process up to manufac­ turing level. In their laboratory, they carried A

out a screening process for a human mono­ clonal antibody (mAb) produced by CHO­ cells in the 2L scale. Once the production procedure was established in the DASGIP Benchtop Bioreactor System, they success­ fully scaled­up the process to 100L in a first B

step (Fig. 1), and finally to the 1000L produc­ tion scale, retrieving comparable results in regard to protein quantity and quality.

Reliability and scalability are the crucial parameters in accelerating cell culture procedures for antibody production. Strict­ ly parallel operation in cultivation proc­ esses facilitates fast process development and saves time during laboratory scale ex­ periments. Using controlled benchtop bio­ reactors allows direct comparison of single­ process parameters relevant in cell line de­ velopment or optimisation of the antibody production process itself. Comprehensive data management can further promote ef­ fective use of time.

The main objective was to establish a screening procedure for monoclonal anti­ body­producing CHO cell lines with relia­ ble scale­up properties at the Genmab re­ search facilities in Utrecht. The Cell Line Development team aimed to achieve the same antibody titers in large­scale produc­ tion as were achieved in their small­scale screening cultures, which are fully up and running. They successfully scaled up their process 500­fold.

impact on the industry The case study discussed above demon­ strates that the use of advanced parallel bioreactor systems can accelerate process development in biopharmaceutical science in a smart and comprehensive way. Paral­ lel operations help save time, and lead to reliable results that are easy to scale up.

Parallel design of experiments follows DoE principles, giving an extra plus when aim­ ing for short time­to­market. Depending on the characteristics of the protein of in­ terest, a parallel approach using benchtop bioreactor systems may deliver results that are precisely similar to large scale, allow­ ing operators even to skip a common pilot­ scale development cycle.

D contact Claudia M. Huether DASGIP AG

Fig 1. A: Human mAb-producing cHo cell lines were cultured in a fourfold dAsGIp parallel Bioreactor system using cd-cHo basal media with customized feeding. six independent clones were screened at the 2l scale for cell growth and antibody accumulation. culturing time was 14 days/batch. B: clone #3 was chosen for scale up to 100l+ manufacturing scales.

40_EBSIN3_12_Special_Genmab_DASGIP_tg.indd 40

cHuether@dasgip.de Patrick Priem, Jolanda Gerritsen GenMab N.V. p.priem@genmab.com, gerritsen@genmab.com

01.03.2012 11:38:31 Uhr

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29.02.2012 18:05:00 Uhr

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Nº 3 | Volume 11 | 2012

Euro|Biotech|News

Special: aNtibodieS & MarketS Companion DiagnostiCs

Meeting scientific and regulatory needs Tobias Ostler and Christiane Chène, regulanet®, www.regulanet.com

the majority of drugs are currently prescribed empirically, but advances in research focusing on the molecular mechanisms of specific diseases have opened new pathways to matching patients with drugs that are more likely to be effective and safe. the term ‘personalised medicine’ is currently used to summarise different levels of this process. the route to approval for a drug/diagnostic combination, however, continues to be rocky.

In extreme cases, individualised medicines vary from patient to patient. Such therapeutic concepts include, for example, cell-based cancer vaccines. A less extreme level of personalisation is the concept of stratified medicine. Here, a patient can be classified according to a specific cohort that shows an efficient differential response to a given drug. This stratification is achieved through the use of a clinical biomarker that has been correlated to a differential response.

improving on empirical medicine To be implemented in stratified medicine as a companion diagnostic, a clinical biomarker should be predictive for the efficacy and safety of the treatment. The most frequently-used predictive clinical biomarker concepts at the moment include techniques such as gene-expression pattern, individual protein expression (on histology) and even imaging. A stratified medicine regime adds a clinical biomarker assessment to empirical medicine practice, and associates a patient with the best therapy available with respect to efficacy and safety. That helps to avoid treatments with toxic side effects and low or even no benefit for the patient.

For the application of stratified medicine,

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Blood samples – retrospective biomarker screening is still a common practice.

the following three prerequisites are required: I) underlying disease with variability reflecting multifactorial aetiology, II) multiple treatment options and III) a predictive clinical biomarker.

cetuximab – a pioneer in the field Successful anti-cancer treatment requires not only a potent drug, but also finding the right drug for a specific patient in a timely manner. The concept of stratified medicine has so far therefore focused on cancer treatment where both quality and time are critical. In 2004, the approval of Cetuximab by the US Food & Drug Administration (FDA) added another option for the treatment of colorectal cancer through chemotherapy. However, subsequent clinical

experience indicated benefit for patients in only 10 -20% of the cases. In the years that followed, an intensive search for a predictive biomarker led to stratification of the treatment with Cetuximab. Retrospective analysis revealed a lack of benefit associated with Cetuximab treatment in colorectal cancer patients harboring mutations in the KRAS gene. These studies resulted in a label restriction from both the FDA and the EMA (in 2009) for patients without a KRAS mutation. In Europe, a diagnostic test for detection of the KRAS mutation recently (2011) received a CE label.

Making the case-by-case decision Despite the fact that retrospective clinical biomarker analysis with subsequent development of companion diagnostic tests remains common practice, both the EMA and FDA favor co-development of drug and diagnostic. The concept of co-development envisages the approval of a diagnostic test at the time of drug approval. One of the most important consequences of this concept is that screening for suitable predictive biomarkers should occur at a very early stage of drug development, with implementation of the biomarker hypothesis in clinical trial design. In recent years, both the EMA and FDA have noted the need for regulations and clear concepts to support the development of stratified/personalised medicines along with appropriate diagnostic tests. However, in Europe the situation remains uncertain. Most importantly, current regulations and concept papers do not allow for a coordinated approval of a drug and its associated companion diagnostic.

And in contrast to the situation in the US, cross-labeling of drug and companion diagnostics in Europe is not required. Additionally, self-certification by IVD manufacturers and a lack of harmonised quality regulations in clinical laboratories providing companion diagnostic testing may serve to widen the quality window of test results. Overall, the current regulatory landscape in Europe and in the US implements a case-by-case approach for the development of companion diagnostics that is in line with the advice for a very early consultation with the regulatory agency. B

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You need commitment, focus and passion to find new ways to fight the diseases of this world: innovation is at the heart of it.

Innovation for better health. Our commitment is to bring to patients around the world quality medicines for use in diag­ nosing, combating and preventing disease. Every day we work against time, researching new pathways, new molecules, new technologies – complementing our own capabilities with exper­ tise of innovative partners from science and industry.

The success of this work is evidenced in new medicines for areas with significant unmet medical need such as oncology, cardiovascular and blood diseases, as well as gynecology and ophthalmology. Our aim is a better quality of life for all.

www.bayerhealthcare.com www.bayerpharma.com

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02.09.11 15:13 02.03.2012 14:30:52 Uhr

44

Nº 3 | Volume 11 | 2012

Euro|Biotech|News

Special: aNtibodieS & MarketS Philogen

Armed antibodies to fight cancer Giulio Casi, Philochem AG, Otelfingen, Switzerland

The Philogen group is a specialist for therapies against cancer. Unlike other private companies, the Swiss-italian firm has developed a rich pipeline of antibodies consisting of five different molecules being tested in 15 different clinical trials. The R&D facility in Zurich is run by Philogen subsidiary Philochem, which has specialised in many areas. one of them is the chemical modification of immunomolecules called ‘armed’ antibodies.

tive for the treatment of rheumatoid arthritis. Two registrational studies (one in Phase III and one in Phase II) are in planning. Since it was founded in 2006, Philochem has worked on the following methods for biotechnological product development: – isolation of human monoclonal antibodies from large combinatorial libraries.

– development of armed antibodies (immuno-cytokines and antibody-drug conjugates).

– discovery and validation of vascular markers of pathology using a perfusionbased chemical proteomics approach.

– design, construction and screening of DNA-encoded chemical libraries of unprecedented quality and size.

Since its inception in 1996, the mother company Philogen has focused on the development of new biopharmaceuticals for the treatment of angiogenesis-related disorders. Angiogenesis – the formation of new blood vessels – is a characteristic feature of many severe pathologies such as cancer, rheumatoid arthritis and age-related macular degeneration.

anti-angiogenesis pioneer

Philogen specialises in fighting cancer with modified antibodies that target angiogenesis.

The development of antibody-drug conjugates has recently been receiving a lot of attention, and not only at Philochem, but in the whole biotech industry. With growing generic competition and a lack of new targets, many companies are looking for ways to make antibodies against known targets more efficient. Antibody -drug conjugates represent an interesting therapeutic approach that combines the desirable properties of monoclonal antibodies with the cell-killing activity of cytotoxic drugs, reducing systemic toxicity and increasing therapeutic benefit for patients. In this area, Philogen and its R&D subsidiary Philochem have demonstrated for the first time that a non-in-

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ternalising vascular targeting ADC can be used to mediate strong anti-tumour activity in vivo. The scientists believe that bio-orthogonal reactions that modify proteins at specific sites using cleavable linkages are essential for the development of antibodydrug conjugates. Philochem has developed proprietary traceless site-specific linkage technologies to conjugate novel drugs to clinical-stage human monoclonal antibodies.

phase iii in planning At present, Philogen has four anti cancer antibody derivatives in clinical studies, as well as an antibody-deriva-

The company and its founder Dario Neri have been pioneers in the isolation, engineering and clinical development of lead products capable of targeting angiogenesis in vivo. These technologies are integrated into drug discovery programs. The most promising candidate products are further developed in the Siena-based Philogen facilities. Here production according to GMP standards and clinical trials is conducted with the aim of developing superior products for the imaging and treatment of serious angiogenesis-related diseases.

Philogen and Philochem run three different collaborations with big pharma. Together with Pfizer Inc., Philochem is active in the field of target discovery. It assists Merck Serono in the search for biomarkers by generating monoclonal antibodies.

And self-assembling chemical libraries are in the focus of a co-operation with MedImmune. Philogen is also in negotiations with other pharma partners to out-license its clinical-stage compounds.

B

29.02.2012 18:06:46 Uhr