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MIT Principles & Practice of Drug Management
Monoclonal Antibodiesfor Cancer Therapy
Eunha Kim, Hanna Kuznetsov, Seon Hee Lee, Ryan O'Hara, Karunya Srinivasan
Monoclonal Antibodies for Cancer Therapy
Contents
Introduction ‐ Karunya Srinivasan
Market Analysis ‐ Seon Hee Lee
What is Herceptin? ‐ Ryan O'Hara
Clinical Trials ‐ Hanna Kuznetsov
Considerations ‐ Eunha Kim
Monoclonal Antibodies for Cancer Therapy
MIT Principles & Practice of Drug Management
Introduction‐ Karunya Srinivasan
Monoclonal Antibodies for Cancer Therapy
Antibodies
※ Source: http://people.cryst.bbk.ac.uk/~ubcg07s/gifs/IgG.gif
• Antibodies or immunoglobulins are a crucial component of the immune system, circulating in the blood and lymphatic system and binding to foreign antigens expressed on cells.
• Once bound, the foreign cells are marked for destruction by macrophages and complement.
• Each antibody consists of two heavy chains and two light chains.
• A small region at the tip of the antibody is extremely variable, allowing millions of antibodies with slightly different tip structures to exist. This region is known as the hypervariable region.
Monoclonal Antibodies for Cancer Therapy
Mechanism of Action
※ Source: Nature Reviews Cancer 1, 118‐129 (November 2001)
Monoclonal Antibodies for Cancer Therapy
Antibodies in Cancer Therapy
※ Source: http://www.pipelinedrugs.com/biotechnology_encyclopedia/MonoclonalAb.jpg
• Naked Abs– Alemtuzumab (Campath; Genzyme)
•ADCC/CDC– Rituximab (Rituxan, IDEC)
•non‐hodgkins lymphoma•CD20 antigen•ADCC/CDC
– Trastuzumab (Herceptin,Genentech) •breast cancer•Her2/neu receptor•Blockade of growth factor‐receptor interaction
•ADCC
• Conjugated Abs– Ibritumomab tiuxetan (Zevalin, IDEC)
•non‐hodgkins lymphoma•CD20 antigen
– Gemtuzumab ozogamicin (Mylotarg, Wyeth)
•Acute myelogenic leukemia•CD33 antigen
Monoclonal Antibodies for Cancer Therapy
Mouse, Chimeric, Humanized and Human Antibodies
※ Source: Nature Reviews Cancer 7, 95‐106 (February 2007)
Monoclonal Antibodies for Cancer Therapy
Monoclonal Ab Production
※ Source: Nature Biotechnology 25, 1421 ‐ 1434 (2007)
Mouse Hybridoma Technology
Phage Library for Humanized Abs
Monoclonal Antibodies for Cancer Therapy
Pros and Cons
※ Source: http://www.nature.com/ncprheum/journal/v3/n2/thumbs/ncprheum0424‐f1.jpg
• An ideal tumor cell surface target should be accessible, abundant, homogenous and consistently present on the surface of cancer cells within a tumor.
• Targets should not be highly expressed on normal cells, especially those cells that contitute vital organs so that mAbs can discriminate between normal and cancerous cells.
• Targets should neither be shed from the surface nor be secreted in any form into the circulation.
Monoclonal Antibodies for Cancer Therapy
Small Molecule Inhibitors Vs. Monoclonal Antibodies
Small molecule inhibitors are easily administered(oral Vs intravenous).
Large Molecular weight of mAbs results in lowertissue‐penetration (esp. BBB).
MAbs can act only on the surface and cannot penetratethe cell.
Degradation and clearance is faster for small moleculeinhibitors.
※ Source: Imai and Takaoka Nature Reviews Cancer 6, 714–727 (September 2006)
Monoclonal Antibodies for Cancer Therapy
Currently in the Clinic for Cancer
※ Source: Nature Reviews Drug Discovery 6, 349‐356 (May 2007)
Monoclonal Antibodies for Cancer Therapy
MIT Principles & Practice of Drug Management
Market Analysis‐ Seon Hee Lee
Monoclonal Antibodies for Cancer Therapy
Historical Performance
Over the period 2001‐07, total sales of monoclonal antibody products increased from $3,690m in 2001 to $26,338m in 2007
※ Source: Datamonitor; Company‐reported information
CAGR 37.1%
Monoclonal Antibodies for Cancer Therapy
Forecast Performance
Total sales of the monoclonal market are forecast to increasefrom $26,338m in 2007 to $49,055m in 2013
※ Source: Datamonitor; Company‐reported information
CAGR 10.9%
Monoclonal Antibodies for Cancer Therapy
Historical Product Analysis
※ Source: Datamonitor; Company‐reported information
Monoclonal Antibodies for Cancer Therapy
Historical Product Analysis
Growth driver/resistor products of historical revenue performance:The dominance of the “Big 5” is clearly illustrated below.
※ Source: Datamonitor; Company‐reported information
Monoclonal Antibodies for Cancer Therapy
Herceptin’s Brand Profile
※ Source: Datamonitor; Company‐reported information
Herceptin: Key Facts
Generic name
Mechanism of action
Originator
Marketing companies
Formulation/drug delivery
Approved indications (US)Approved indications (EU)Approved indications (Japan)
US launchEU launchJapan launch
2007 sales, 7MM
Trastuzumab
HER‐2‐directed MAb
Genentech
Genentech, Roche, Chugai
Intravenous
Breast cancerBreast cancerBreast cancer
199820002001
$2,653m
Monoclonal Antibodies for Cancer Therapy
Forecast Sales of Herceptin
※ Source: Datamonitor; Company‐reported information
Monoclonal Antibodies for Cancer Therapy
Genentech’s Big Three
※ Source: Datamonitor; Company‐reported information
Monoclonal Antibodies for Cancer Therapy
MIT Principles & Practice of Drug Management
What is Herceptin?‐ Ryan O'Hara
Monoclonal Antibodies for Cancer Therapy
Herceptin: Structure
※ Source: Images from PDB, edited with PyMol.
Trastuzumab: anti‐HER2 humanized monoclonal antibody
Herceptin bound to HER2 receptor, blocking binding to EGF
Monoclonal Antibodies for Cancer Therapy
Proposed Mechanisms ofHerceptin ActionExact mechanisms are incompletely definedEfficacy determined through clinical trials (general effects observed)Proposed to have multiple, interconnected mechanismsMolecular and cellular effects observed in vitro and in vivoGeneralization: ‐‐ Promotes anti‐cancer factors ‐‐ Inhibits pro‐cancer factors
※ Source: Rita Nahtaa, Francisco J. Esteva (2005)
Monoclonal Antibodies for Cancer Therapy
Proposed Mechanisms ofHerceptin Action
Internalization and degradation of HER‐2.Disrupts receptor dimerization; disruptsdownstream signaling pathways
G1 arrest and reduced proliferation.Induces p27kip1‐cdk2 complex formation;induces p27kip1 levels
Promotion of Apoptosis
Suppression of angiogenesis: (reducedexpression of VEGF, TGF‐a, Ang‐1,)
Induction of anti‐angiogenic factors (TSP‐1)
Induces Immune‐mediated responses:‐ ADCC; stimulates natural killer cells
Inhibits HER‐2 ECD proteolysis
Inhibits DNA repair – (synergistic effectwhen combined with chemo, radiationtherapies)
※ Source: Rita Nahtaa, Francisco J. Esteva (2005)
Monoclonal Antibodies for Cancer Therapy
Characteristics of HerceptinAs a Cancer Therapy
Advantages
Synergistic effect with othertreatments
Targets HER‐2 overexpression:‐ effective in primary tumor andmetastatic sites.
Severe HER‐2 overexpression incancerous cells reducedoff‐target effects
Flexible usage, being approvedfor other cancers, with othertreatments etc..
※ Source: Rita Nahtaa, Francisco J. Esteva (2005)
Disadvantages
Risk of fatal infusion reaction
Reduction in Heart function
Complications for pregnant women
Relapse/resistance after 1 yearon average
Effective only in 20‐25% of invasivebreast cancers
Monoclonal Antibodies for Cancer Therapy
MIT Principles & Practice of Drug Management
Clinical Trials‐ Hanna Kuznetsov
Monoclonal Antibodies for Cancer Therapy
Herceptin: Clinical Trials
※ Source: Herceptin.com
Doxorubicin + Cyclophosphamide Paclitaxel (AC‐Pac) vs. Doxorubicin + Cyclophosphamide Paclitaxel + Herceptin (AC‐PacH)12 weeks52% lower risk of recurring breast cancer
1. Adjuvant Breast Cancer
Same as above52 weeks
2. Adjuvant Breast Cancer
Monoclonal Antibodies for Cancer Therapy
Herceptin: Clinical Trials
※ Source: Herceptin.com
4 chemotherapy cycles vs.1 year Herceptin46% lower recurrence rate
3. Adjuvant Breast Cancer: following surgery
A. DuctsB. LobulesC. Dilated section of duct to hold milkD. NippleE. FatF. MuscleG. Chest wall/rib cage
Monoclonal Antibodies for Cancer Therapy
Herceptin: Clinical Trials
(ER/PR negative, tumor > 2 cm, age < 35 yrs, histological/nuclear grade 2 or 3, etc)
• Doxorubicin + Cyclophosphamide Docetaxel (AC‐T) vs.Doxorubicin + Cyclophosphamide Docetaxel + Herceptin (AC‐TH) vs.Docetaxel + Caroplatin + Herceptin (TCH)
• 33% lower overall recurrence rate
4. Adjuvant Breast Cancer: at least 1 high‐risk factor
※ Source: Herceptin.com; gene.com
Monoclonal Antibodies for Cancer Therapy
Herceptin: Clinical Trials
※ Source: Herceptin.com
Chemo vs. Chemo + Herceptin
5. Metastatic Breast Cancer: previously untreated for metastasis
Weekly Herceptin doses
6. Metastatic Breast Cancer: previously treated and relapsed
Monoclonal Antibodies for Cancer Therapy
Choosing Herceptin?
Potential ProblemsHeart problems‐‐ Reduced heart function‐‐ Congestive heart failure‐‐ Highest risk in Herceptin + anthracycline therapy‐‐ If heart function drops significantly, stop treatment‐‐ If existing heart condition, don’t use drug
Infusion / lung problems‐‐ Risk of fatal infusion reaction within 24 hours of treatment‐‐ If low blood pressure or shortness of breath, temporarily suspend treatment‐‐ If severe allergic reaction or lung problems, stop treatment
Pregnant women‐‐ Treatment may be harmful to fetus‐‐ Lowers amniotic fluid levels‐‐ Choose to stop treatment or stop breast‐feeding as mAb’s can be transferred
Side Effects
Monoclonal Antibodies for Cancer Therapy
Biomarkers: Future of Personalized Medicine
• Diagnostic- Define a population w/ specific disease, differentiate
stages of disease
• Prognostic- Correlate with clinical outcomes
• Predictive- Defining population w/ better drug safety/efficacy
• Response- Efficacy- Toxicity- Mechanism- Target
• Translation- Preclinical and clinical settings
• Surrogate- Valid substitute for a clinical outcome
• Breast Cancer- Established / routine: estrogen receptor, progesterone
receptor, HER2- Potential future clinical use: EGF receptor, Ki‐67,
topoisomerase IIa
• Immunohistochemistry (IHC):Measure protein expression levels and localization in a diseased tissue.Measure overexpression of HER2 receptors.
• Fluorescent in situ hybridization (FISH):Measure gene amplification.“Gold standard” for measuring number of HER2 receptor genes.
Monoclonal Antibodies for Cancer Therapy
MIT Principles & Practice of Drug Management
Considerations‐ Eunha Kim
Monoclonal Antibodies for Cancer Therapy
Side Effects
※ Source: www.cancer.org
Cytotoxic ChemotherapyHas toxicities to various organs : rapid proliferating cells of the oral and intestinal mucosa, bone marrow, hair follicles
Some of the most common possible side effects include: hair loss, mouth sores, loss of appetite, nausea and vomiting increased chance of infections (due to low white blood cell counts) easy bruising or bleeding (due to low blood platelet counts) fatigue (due to low red blood cell counts and other reasons)
Monoclonal Antibody Therapy Side EffectsCompared with side effects of chemotherapy, the side effects of nakedmonoclonal antibodies are usually fairly mild and are often related to an allergic type reaction. If they do occur, it is most often while the drug is first being given.
Possible side effects: fever, chills, weakness, headache, nausea, vomitting,diarrhea, low blood pressure, rashes
Monoclonal Antibodies for Cancer Therapy
Prevention of Metastasis andDisease Prognosis
※ Source: Dean‐Colomb and Esteva, EJC (2008)
A number of clinical trials showed…‐‐ trastuzumab administration in combination with or subsequently afterchemotherapy resulted in an improvement in disease‐free and overall survival
Two major phase II clinical trials (leading to FDA approval)‐‐ 248 heavily pretreated HER2 positive metastatic breast cancer (MBC) patients‐‐Overall response rate (ORR) to trastuzumab was 12‐15%
Trastuzumab as a first‐line single agent in HER2 positive MBC‐‐ORR was 19‐26%
Trastuzumab + other chemotherapeutic agents (ie. Paclitaxel, anthracycline) in MBC‐‐ significant increase in time to disease progression, ORR, overall survival‐‐ 20% reduction in the risk of death
Herceptin in Metastatic Setting
Monoclonal Antibodies for Cancer Therapy
Prevention of Metastasis andDisease Prognosis
※ Source: Dean‐Colomb and Esteva, EJC (2008)
Evaluation of Trastuzumab in the Adjuvant Setting in Early Breast Cancer
Monoclonal Antibodies for Cancer Therapy
Prevention of Metastasis andDisease Prognosis
※ Source: Cosimo and Baselga, EJC (2008)
A Current Combinatorial Therapy Trial: neo‐ALTTO Study
Lapatinib (Tykerb): dual action tyrosine kinase inhibitor of both EGFR1 and HER2
Monoclonal Antibodies for Cancer Therapy
Potential Future of MAb
※ Source: Oldham and Dillman, Journal of Clinical Oncology (2008)
Clinical toxicities with murine monoclonal antibodies
The major limitation of murine monoclonal antibody therapy : the immunogenicity of the mouse protein
Humanized antibodies are necessary for monoclonal antibody therapyto be successful
Monoclonal Antibodies for Cancer Therapy
Potential Future of MAb
※ Source: Oldham and Dillman, Journal of Clinical Oncology (2008)
Two types of monoclonal antibodies used in cancer treatment‐‐ naked monoclonal antibodies without any attachment‐‐ Conjugated monoclonal antibodies with chemotherapy drug, radioactive particle, or a toxin.
Naked monoclonal antibodies
Monoclonal Antibodies for Cancer Therapy
Potential Future of MAb
※ Source: www.cancer.org
Radiolabeled antibodies‐‐ Ibritumomab tiuxetan (Zevalin). delivers radioactivity directly to cancerous B lymphocytes. used to treat B cell non‐Hodgkin lymphoma that has not responded to standard treatment
‐‐ Tositumomab (Bexxar) . used to treat certain types of non‐Hodgkin lymphoma that no longer respond to Rituximan or chemotherapy
Chemolabeled antibodies ‐‐ bacterial/plant toxins are attached to monoclonal antibody ‐‐ available in the US only through clinical trials at this time‐‐ clinical trials show promising results
ie. Immunotoxin BL22 in treating chronic leukemia patients who no longer responded to chemotherapy
‐‐ Gemtuzumab (Mylotarg): the only approved immunotoxin
Monoclonal Antibodies for Cancer Therapy
Potential Future of MAb
※ Source: www.cancer.org; Bell and Cameron, EJC Supplements (2008)
Bevacizumab (Avastin): humanized anti‐VEGF monoclonal antibody(First angiogenic agent shown to benefit MBC when combined with chemotherapy)
Monoclonal Antibodies for Cancer Therapy
Potential Future of MAb
※ Source: Oldham and Dillman, Journal of Clinical Oncology (2008)
Treatment of advanced breast cancer is complex
Desirable treatment endpoints‐‐ prolongation of survival, achieving symptomatic control, tumor shrinkageand maintaining quality of life
Targeted therapy to balance efficacy of treatment with its toxicity
Currently available targeted therapy : trastuzumab, bevacizumab, lapatinib
Application of immunotherapy in other diseases
Monoclonal Antibodies for Cancer Therapy※ Source: http://en.wikipedia.org/wiki/Monoclonal_antibody_therapy
MIT Principles & Practice of Drug Management
Thank You!