Monoclonal Antibody For Cancer Treatment: A Regulatory Affairs Professional's Perspective

Monoclonal Antibody for Cancer Treatment: A Regulatory Affairs Professionals Perspective Lewis Lau & Vadim Lysenko, 2012
All Rights Reserved Regulatory Affairs Program, Humber College, Toronto, ON
1.0 Introduction Over a century, scientists have never stopped the quest for the magic bullets(magische kugel) for pathogens, as the concept was first popularized by German Nobel laureate Paul Ehrlich in the 1890s. Moving into 2012, the idea of magic bullets remains appealing and seems to be evolving as we proceed to a new chapter in the recent developments in monoclonal antibody (mAb) therapeutics, particularly in the field of oncology. In conventional cancer treatment, chemotherapeutics induce cell death in cancer cells but the drug class lacks specificity totargets, as the cytotoxicity is not limited to cancer cells but to all the other fast-dividing cells. Aided by the advance in protein engineering, a paradigm shift in cancer therapy is quickly approaching as non-selective chemotherapeutics are being replaced by mAb with high affinity to specific targets with improved safety and immunogenicity profile. In this article, we will further discuss various aspects of the drug class, including the advance development of the technology, its clinical significance, impact to the pharmaceutical market, as well as its implication to regulatory affairs professionals.
Monoclonal Antibody for Cancer Treatment: A Regulatory Affairs Professionals Perspective Lewis Lau & Vadim Lysenko, 2012 All Rights Reserved Regulatory Affairs Program, Humber College, Toronto, ON
1.1 History of mAb Development The mAbtherapy development in the modern world dates back to 1890, when Kitasato and Behring first reported the use of anti-serum therapy for diphtheria. Their effort helped to stop the 1984 epidemic of diphtheria, which took the lives of more than 50,000 children annually in Germany alone. Despite of the technological breakthrough at the time, the use of anti-serum suffers from several major setbacks, including the side effects of immunogenicity and low yield in antibody production1.Fortunately, Khler, Milstein and Jerne succeeded in develop the method of isolating mAbs by hybridroma technology in 1975, which symbolized a significant improvement in antibody yield. These scientists were awarded the Nobel Prize in Medicine and Physiology in 1984. However, the issue of immunogenicity remained as most mAb developed at the time were originated from mice, where development of anti-mouse antibodies in cancer patients can be easily observed after a few infusion of the drug. Therefore, a movement in developing human or humanized antibodies, instead of murine antibody, is initiated in order to bring forth a successful mAb therapeutic for cancer. In the US, mAb therapy use was first reported in a patient of non-Hodgkins lymphoma in 1980. Although treatment was not successful, the study represented the first proof-of-principle of mAb therapy in human for inducing transient decreases in the number of circulating tumor cells, as well as the formation of complexes with circulating antigen with minimal toxicity2. Later on, humanization of antibody was made possible by replacing the V chains of murine antibody to a more human-like region to lower immunogenicity profile of the antibody. Since the 1980s, significant improvement in generating humanized mAbs and identification of novel targets was made, aided by the advance in molecular biology and techniques, including phage-
display, transgenic animal and protein engineering. Currently, 22 mAbs are approved by the US FDA and more than thousands of candidates in the pipeline. As presented in Table 1, a short list of mAb for cancer indicated for various types of cancer is provided. The newer humanized or chimeric mAbs have a longer half-life in the blood stream, and they are able to interact with human complement or effector cells of the patients immune system owing to the similar to naturally occurring immunoglobulin. Hence, these mAb work collaboratively with the patients immune response to target cancer cells effectively2.
1.2 Market Trends In 2007, mAbs hold 8 of the top 20 best-selling biotechnology drugs with a growth rate of more than 35%3.This trend is expected to sustain with the future development in antibody engineering. As presented in Table 2, many of the mAb drugs is forecast to be included in the top 50 bestselling drugs, where 4 of them are indicated for cancer therapy4.
1.3 Mechanisms of Action and Clinical Significances Various types of cancer cell exhibit overexpression of membrane-bound receptors for growth factors. As the growth factors are important in controlling the cell proliferation and differentiation, the overexpression of the corresponding receptor may result in over-stimulation of the receptor at the cell surface, leading to a series of downstream cell signalling cascades. This attribute is commonly seen in many types of cancer cell, which grow and divide in uncontrolled manner. Provided with the article is a video to illustrate this characteristic of the cancer cell (Video available on URL: http://yunpan.cn/lk/sVWd2HFbCP65X). Aided by basic research and advance of technology, many of over-expressed receptors that are related to the deregulated cell proliferation are now identified in various subtypes of cancer. Preclinical studies and clinical trials are taking place to develop mAb to target these receptors. Essentially, most mAb cancer therapeutics can be characterized by three mechanisms of tumour cell killing, as summarized by Scott et al5. The first mechanism entails the direct action of antibody by receptor blockade or activation, leading to the induction of apoptosis. The second mechanism is mediated by the immune system through the complement-dependent cytotoxicity (CDC) pathway or the antibody-dependent cellular cytotoxicity (ADCC) as illustrated in Fig. 1.The final mechanism proposed was the induction of vascular and stromal cell ablation by the binding of mAb to vasculature receptors. A recently approved drug product Removab (catumaxomab) is an example to illustrate the exceptional safety and efficacy of mAb in cancer treatment.
Catumaxomab is indicated for the palliative management of malignant ascites (MA) via intraperitoneal infusion in patients with epithelial cell adhesion molecule (EpCAM) positive carcinomas, where standard therapy is not available or no longer feasible. Generally, the relationships of MA and catumaxomab can be described the following: 1) epithelial tumors spreading into the peritoneal cavity play a major role in the development of MA; 2) epithelial tumors express EpCAM; 3) in the peritoneal cavity, EpCAM is a tumorspecific antigen for catumaxomab; and 4) immune effector cells of catumaxomab are present in MA6. As catumaxomab is a tri-functional antibody (trAb) characterized by its unique ability in binding three different cell types: tumor cells, T-cells, and accessory cells. The mAb binds to epithelial cell adhesion molecule (EpCAM) on tumor cells, the CD3 antigen on T-cells, and to type I, IIa, and III Fc receptors (FcRs) on accessory cells (e.g. natural killer cells, dendritic cells, and macrophages)7.This results in direct recruitment and activation of potent immune cells to the cancer cells, leading toT-cell-mediated lysis, antibody-dependent, cell-mediated cytotoxicity, and phagocytosis via activation of FcR-positive accessory cells7. Catumaxomab represents a selfsupporting system, as no additional immune cell activation is required for tumor eradication. This unique property of Catumaxomab is shown in Fig.2. Prior to the approval of catumaxomab, no agents were specifically approved for the treatment of MA. Therefore, the ability of catumaxomab to bind three different moieties displayed asignificant breakthrough in antibody specificity. A pivotal phase II/III, multicenter, two-arm, randomized (2:1), open-label study compared catumaxomab plus paracentesis with paracentesis alone (control) in patients who were resistant
to chemotherapy and who had at least one previous puncture within 5 weeks before screening, as well as symptomatic ascites and EpCAM-positive tumor cells in the ascites. The primary endpoint was puncture-free survival, defined as the time after day 0 (control group)/1 day after last infusion (catumaxomab group) to the first need for therapeutic paracentesis or death, whichever occurred first. Secondary endpoints included time to next therapeutic paracentesis, ascites signs and symptoms, and safety. Results demonstrated that catumaxomab was efficacious and significantly prolonged puncture-free survival versus paracentesis alone in the intent-to-treat population6. (Results on URL: http://www.jcancer.org/ms/getimage.php?name=jcav02p0309g03.png) Interestingly, catumaxomab, a partial murine monoclonal antibody, was not associated with any major safety issues in this study. In fact, the development of human anti-mouse antibodies (HAMAs) is suggested to be associated with beneficial immunity and prolonged survival8. Investigators suggested that HAMAs, in the use of catumaxomab in treating MA per se, may be promoting survival by inducing a series of immune cascade to aid recruitment of cytotoxic mAbs to the cancer target. As reflected by the results of the post-hoc analysis of the pivotal phase II/III trial, positive clinical outcome and humoral response using HAMAs as a biomarker is strongly correlated9. (Results on URL: http://www.jcancer.org/ms/getimage.php?name=jcav02p0309g05.png) These results demonstrate the advances in mAb technology in improving clinical outcomes of previously untreatable cancer conditions, and also suggest that immunogenicity of murine antibodies should not a priori preclude the use of mAb in cancer therapy.
2.0 Canadian Regulatory Requirements, Patent Law and Research In Canada, the mAb products are regulated as biologics, as the requirements are mostly outlined in the Food and Drug Regulations (FDR). The recently revised version of Manual of Patent Office Practice (MOPOP) also has a specific set of requirement in applying patent for intellectual properties protection. On the other hand, the National Research Council Canada offers custom antibody service for a wide range of clients to promote incentive for research in basic sciences.
2.1 Regulatory Requirements in Canada Being a biologic, manufacturers of mAbs must comply with the regulatory requirements outlined in Section C.04 of FDR. In the New Drug Submission (NDS), the manufacturer is required to provide product-specific facility information to describe the method of mAb manufacturing as well as chemistry and manufacturing information in great details. Also, the manufacturer needs to submit a draft label of the product with specific requirements for biologics. The manufacturing facility of the product is subjected to pre-approval on-site evaluation (OSE) to access compliance to GMP, quality of manufacturing process and quality control. mAb products are subjected to different levels of evaluation by the Lot Release program depending on the risk profile. Under the program, BGTD of Health Canada may request sample for testing and review testing protocol. Should the manufacture facility undergo any changes which may affect the safety, efficacy and quality of the mAbs, the manufacturer may be required to provide additional information of the changes or even to file a supplemental NDS (SNDS) depending on the level of the change. Last but not least, a Yearly Biologic Product Report has to
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be submitted to Health Canada annual to evaluate the consistency in the process of mAb production.
2.2 Patent Law in Canada Prior to the current update in the MOPOP in 2009 by the Canadian Intellectual Property Office (CIPO), patent application for mAb against a novel antigen required a working example with evidence of actual production of mAb as required by Patent Rule Section 80(1)(f)10. This is not a requirement for patent application for mAb in other major markets such as US and Europe, where a claim to the mAb is made usually based on the immunogenicity to the novel antigen. In the past, there were cases that patent claims of mAb against novel antigen being rejected in Canada, as the applicant failed to provide evidences of mAb production at the filing date. The 2009 revised version of Chapter 17 in the MOPOP now indicates that a working example is not necessary for a mAb against a novel antigen in applying patent in Canada, given the specification of the structural description of the particular epitope on the antigen where the mAb binds11. This change led to the successful patent claim for the antibody against IL-1R polypeptide by Immunex (Patent Application No. 583,988) in 2011, which failed to claim patent in 1988 due to the lack of evidence in mAb production12. This change is welcome by the industry as it brings Canada in line with jurisdiction of US and Europe.
2.3 National Research Council Canada National Research Council (NRC) plays a leading role in providing Canada with strategic Science & Technology (S&T) information, intelligence and connections to centres of advanced S&T around the world. The NRC Custom Antibody Facility in particular, provides expertise and high-quality production of monoclonal and polyclonal antibodies for Canadian and international clients and partners. It helps small and large enterprises overcome workforce constraints and limited resources, accelerating design cycles and helping to identify product performance limits. The customer usually supplies the antigen, even though the NRC Peptide Synthesis Facility can prepare it according to their needs. The Monoclonal Antibody Facility integrates extensive knowledge in the production of monoclonal antibodies against a variety of antigens such as peptides, purified proteins, whole cells, membranes, carbohydrates and small molecules. NRC plays an important role in driving the advancement of custom antibody technology.
3.0 Future Developments and Challenges In spite of the high specificity to target and improvements in reducing immunogenicity, mAb used as treatment for cancer still process certain level of toxicity. For instance, Trastuzumab is associated with an increased risk cardiotoxicity in women with metastatic breast cancer, where the incident rate of cardiac dysfunction is 13% when used in combination with paclitaxel, and 27% when used in combination with anthracycline13. On the other hand, an IgG molecule of mAb, which is as large as 150 kDa, is considered relatively large compared with traditional small molecule drugs. This limits the distribution and penetration of the mAb to solid tumours as a result of compacted stroma and high intra-tumour pressure by the lymphatic return barrier. High volume of quality research in antibody engineering and clinical trials are currently on the way to improve existing antibodies and investigate the possibility to broaden the indication to multiple malignancies. The possibilities of combining mAb technology with gene therapy, or by exploiting mesechymal stem cells have been discussed14. More interestingly, there is a significant amount of discussions in developing antibody-like biologics, which means exploiting the structure of various antibody fragments to design biologic molecules with high specificity to target. The most recent Next Generation Protein Therapeutic Summit held in San Francisco, CA, presented some of the latest technologies in developing drug in this aspect. For instance, Swedish biotech company Affibody is developing antibody-mimetic molecule, which claims to be as small as 6 kDa in size15. Belgian biotech company Complix offers full platform to design antibody-mimetic molecules, in silico, which is 10-14 kDa in size and holds a melting temperature above 120 oC16. Some companies departed from exploiting the structure antibody technology, where they invest in alternative approaches. A great example is German company
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Scil Proteins, in which they attempted in making antibody-like biologics based on the structure of Ubiquitin protein17.
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4.0 Conclusion In summary, the use of mAb therapeutics in the treatment of cancer is quickly expanding owing to many advantages offered by the drug class, including but not limited to the high specificity to target and minimal toxicity. The development in antibody engineering and other molecular biology techniques allowed significant improvement in antibody yield as well as reduction of the immunogenicity. The list of approved mAb offers treatment option for a wide range of malignancy. This expanding list of mAb and the illustrated example, Removab, demonstrated the clinical significance of mAb in cancer treatment. Further, the drug class is forecasted to generate high revenue, as more of its kind will be made available in the market in the future. In Canada, manufacturers of mAb are required to comply with various regulatory requirements as mandated by the FDR. Currently revised chapter of MOPOP specific to mAb has provided more welcoming procedures in applying patent for mAb technology against novel antigens. Also, National Research Council Canada offers custom antibody service in promoting research in the field. Moving forward, future development aims to reduce immunogenicity profiles, toxicity profile, and enhance bioavailability of mAb. Further, the unique properties of mAb have inspired scientist to develop future designers biopharmaceutics.
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References 1. Dimitrov DS, Marks JD. Therapeutic antibodies: current state and future trends--is a paradigm change coming soon? Methods Mol Biol. 2009;525(1-27):xiii. 2. Oldham RK, Dillman RO. Monoclonal antibodies in cancer therapy: 25 years of progress. J Clin Oncol. 2008;26(11):11747. 3. Scolnik PA. mAbs: a business perspective. MAbs. 2009;1(2):17984. 4. World Preview 2018 - Embracing the Patent Cliff. London, UK: EvaluatePharma; 2012. 5. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):27887. 6. Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV, Dudnichenko AS, Aleknaviciene B, Razbadauskas A, Gore M, Ganea-Motan E, Ciuleanu T, Wimberger P, Schmittel A, Schmalfeldt B, Burges A, Bokemeyer C, Lindhofer H, Lahr A, Parsons SL. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int J Cancer. 2010;127(9):220921. 7. Seimetz D. Novel Monoclonal Antibodies for Cancer Treatment: The Trifunctional Antibody Catumaxomab (Removab). J Cancer. 2011;2:30916. 8. DeNardo GL, Bradt BM, Mirick GR, DeNardo SJ. Human antiglobulin response to foreign antibodies: therapeutic benefit? Cancer Immunol Immunother. 2003;52(5):30916. 9. Ott MG, Lindhofer H, Linke RG, et al. The trifunctional antibody catumaxomab: Correlation between immunological response and clinical outcomeNew analysis of a pivotal phase II/III study. J Clin Oncol. 2010;28(Suppl):Abstract 2551. 10. Patent Rule. 1996. 11. Manual of Patent Office Practice. 2009. Available at: http://www.ic.gc.ca/eic/site/cipointernet-internetopic.nsf/eng/h_wr00720.html. 12. Sally A. Hemming. Canadian Patent Office grants claims to monoclonal antibodies without a working example. Toronto, Ontario: Smart & Biggar/Fetherstonhaugh; 2011. Available at: http://www.smart-biggar.ca/en/articles_detail.cfm?news_id=445. 13. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):121521. 14. Zhang Q, Chen G, Liu X, Qian Q. Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy. Cell Res. 2007;17(2):8999.
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15. Affibody Product Portfolio: Technology. Available at: http://www.affibody.com/en/ProductPortfolio/. 16. Complex Alphabody Therapeutics: Technology. Available at: http://www.complix.be/technology_properties.htm. 17. Scil Proteins Affilin Technology. Available at: http://www.scilproteins.com/en/AffilinTechnology.
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Table 1. Examples of approved MAb for cancer therapy Product Avastin Generic Name bevacizumab Company Roche Indication metastatic colorectal cancer CD20 positive NHL B-cell chronic lymphocytic leukemia Imaging agent for metastatic colorectal cancer metastatic colorectal cancer HER2-overexpressed metastatic breast cancer Human antibody linked to chemotherapeutic of calicheamicin for CD33-positive AML CD20-positve NHL FDA Approval Feb. 2004 Jun. 2006 Oct. 2006 Jun. 2003 Jan. 2005 May. 2001
BEXXAR Campath
tositumomab and tositumomab I-131 alemtuzumab
Coriza Corp. and GSK Millenium Pharmaceuticals, Inc. and Berlex Laboratories, Inc. Immunomedics, Inc.
CEA-Scan
acritumomab; technetium-99 labeled cetuximab
Jun. 1996
Erbitux
Herceptin
trastuzumab
ImClone Systems Inc. and BristolMyers Squibb Genentech, Inc.
Feb. 2004 Mar. 2006 Sep. 1998
Mylotarg
gemtuzumabozogamicin
UCB and Wyeth
May 2000
Rituxan
rituximab
Biogen Idec and Genentech, Inc.
RG1273
pertuzumab
Roche
Vectibix Zevalin
panitumumab ibritumomabtiuxetan
Amgen IDEC Pharmaceutical Corp.
HER2-overexpressed metastatic breast cancer Metastatic colorectal cancer Low grade B-cell NHL, MAb combined with radioactive Y-90
Nov. 1997 Feb. 2006 Feb. 2006 Sep. 2006 Sep. 2006 N/A*
Sep. 2006 Feb. 2002
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Table 2.mAbs with cancer indications listed in global top 50 best selling drug products forecast by EvaluatePharma Rank 3 Product Rituxan Generic Name rituximab Company Roche + Biogen Idec Roche Roche Roche Pharmacological Class Anti-CD20 MAb Anti-VEGF MAb Anti-HER2 MAb Anti-HER2 MAb Sales 2011 ($M) 3078 2649 1608 0* Sales 2018 ($M) 3161 2962 1792 2482
5 Avastin bevacizumab 23 Herceptin trastuzumab 36 RG1273 pertuzumab Source: EvaluatePharma, 2012.
Table 3. Comparison of past and current practices in patent application for mAb in Canada Past Practice Requirements Claim directed to mAb only if specification includes at least one working example demonstrating the preparation mAb 2009 Revised Chapter 17, MOPOP Working example is not absolutely essential. However, specification must include a structural description of particular epitope on the antigen to which the MAb specifically binds, in order to describe the Mab sufficiently. Canada is put in line with other major foreign jurisdiction (US, Europe), no working example is essential in making patent claims for mAb. More ease in claiming innovative mAb product leads to incentive in investing in Canadian market.
Significance
Most foreign jurisdictions (US, Europe) allow claim to mAb in terms of immunoreactivity with defined antigen, where no working example is required. Poor patent protection in Canada compared to other major markets, leading to decreased incentive in investing in Canadian market.
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Fig. 1. Immune-mediated mechanisms in tumour cell death by mAbs. (a)left-hand panel illustrates the ADCC pathway, where mAb is recognized by the Fc receptor of an effector cell (NK cell in this example). The NK cell then releases cytokines and other signalling molecules to promote cell death of the targeted cancer cell. (b)right-hand panel illustrate the CDC pathway, where mAb triggers an assembly of c1-complex. The complex initiates the formation of membrane attack complex (MAC), which forms a transmembrane channel on the targeted cancer cell, leading to osmotic lyses of the cell.
Fig. 2. Schematic diagram showingcatumaxomab`s mechanism of action. ADCC = antibody-dependent cellmediated cytotoxicity, EpCAM = epithelial cell adhesion molecule, Fc R = Fc receptor, IL = interleukin, NK = natural killer.
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Monoclonal Antibody For Cancer Treatment: A Regulatory Affairs Professional's Perspective

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Monoclonal Antibody for Cancer Treatment: A Regulatory Affairs Professionals Perspective Lewis Lau & Vadim Lysenko, 2012

All Rights Reserved Regulatory Affairs Program, Humber College, Toronto, ON

tositumomab and tositumomab I-131 alemtuzumab

acritumomab; technetium-99 labeled cetuximab

ImClone Systems Inc. and BristolMyers Squibb Genentech, Inc.

Feb. 2004 Mar. 2006 Sep. 1998

UCB and Wyeth

Biogen Idec and Genentech, Inc.

Amgen IDEC Pharmaceutical Corp.

Sep. 2006 Feb. 2002

5 Avastin bevacizumab 23 Herceptin trastuzumab 36 RG1273 pertuzumab Source: EvaluatePharma, 2012.

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