monoclonal antibodies for cancer...

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



Introduction‐ Karunya Srinivasan


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.


Mechanism of Action

※ Source: Nature Reviews Cancer 1, 118‐129 (November 2001)


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


Mouse, Chimeric, Humanized and Human Antibodies

※ Source: Nature Reviews Cancer 7, 95‐106 (February 2007)


Monoclonal Ab Production

※ Source: Nature Biotechnology 25, 1421 ‐ 1434 (2007)

Mouse Hybridoma Technology

Phage Library for Humanized Abs


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.


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)


Currently in the Clinic for Cancer

※ Source: Nature Reviews Drug Discovery 6, 349‐356 (May 2007)



Market Analysis‐ Seon Hee Lee


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%


Forecast Performance

Total sales of the monoclonal market are forecast to increasefrom $26,338m in 2007 to $49,055m in 2013


CAGR 10.9%


Historical Product Analysis



Historical Product Analysis

Growth driver/resistor products of historical revenue performance:The dominance of the “Big 5” is clearly illustrated below.



Herceptin’s Brand Profile


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


Forecast Sales of Herceptin



Genentech’s Big Three




What is Herceptin?‐ Ryan O'Hara


Herceptin: Structure

※ Source: Images from PDB, edited with PyMol.

Trastuzumab: anti‐HER2 humanized monoclonal antibody

Herceptin bound to HER2 receptor, blocking binding to EGF


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)


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)



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..


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



Clinical Trials‐ Hanna Kuznetsov


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




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



(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




Chemo vs. Chemo + Herceptin

5. Metastatic Breast Cancer: previously untreated for metastasis

Weekly Herceptin doses

6. Metastatic Breast Cancer: previously treated and relapsed


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


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.



Considerations‐ Eunha Kim


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


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



※ Source: Dean‐Colomb and Esteva, EJC (2008)

Evaluation of Trastuzumab in the Adjuvant Setting in Early Breast Cancer



※ 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


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




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



※ 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



※ 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)




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


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