• Information
  1. Overview of Uses
  2. Anti-CD3
  3. Anti-IL2 Receptor MAbs
  4. Tumor Necrosis Factor alpha Blockers
  5. Trastuzumab
  6. Anti-CD20 MAbs
  7. Cetuximab
  8. Panitumumab
  9. Anti-alpha4 Integrin MAb
  10. Anti-CD52
  11. Anti-CD33 MAb
  12. Tocilizumab
  13. Omalizumab
  14. Bevacizumab
  15. Ranibizumab
  16. Ustekinumab
  17. Anti-RSV MAb

A. Overview of Uses

1. Increasing development of MAbs for human disease
2. Both acute and chronic uses have been pursued
3. Most are administered as intravenous therapy
4. "Humanized" MAbs are usually used clinically
   1. Chimeric MAbs have mouse Fab (antigen binding) region with human Fc
   2. Humanized MAbs have humanized Fab (mouse CDR + human framework) and human Fc
   3. Fully human MAbs are now produced in transgenic mice
5. Transplantation
6. Rheumatologic / Autoimmune Disorders
7. Oncology - Approved MAbs [1]
   1. Alemtuzumab (Campath®): anti-CD52 on lymphocytes
   2. Bevacizumab (Avastin®): anti-VEGF
   3. Cetuxumab (Erbitux®): anti-EGF-R on colorectal (and other) cancers
   4. Gemtuzumab ozogamicin (Mylotarg®): anti-CD33 with colicheamicin derived toxin for AML
   5. Ibritumomab tiuxetan (Zevalin®): anti-CD20 radiolabeled (Yt-90)
   6. Panitumumab (ABX-EGF): anti-EGF-R
   7. Rituximab (Rituxan®): anti-CD20
   8. Tositumomab (Bexxar®): anti-CD20 radiolabeled (I-131)
   9. Trastuzumab (Herceptin®)
8. Infectious Disease - anti-RSV MAb (see below)
9. Cardiology (GP IIb/IIIa Blockade)

B. Anti-CD3 (muromonab, Orthoclone OKT3®)

1. Murine MAb for prevention of organ graft rejection
2. Used both first line and for glucocorticoid resistant rejection
3. Some studies have shown improved long term graft survival
4. Dose is 5mg/d intravenous
5. Increased rates of infection, cytokine release syndrome, and anti-mouse antibodies
6. Chimeric and humanized anti-CD3 Abs are in development

C. Anti-IL2 Receptor MAbs

1. Daclizumab (Zenapax®) [2]
   1. This is a humanized (IgG1 Fc) anti-IL2R alpha chain (CD25) Ab
   2. Reduces acute rejection episodes in moderate and high risk patients
   3. Reduced biopsy proven acute rejection from 35% to 22% in combination with other drugs
   4. Used in combination with CsA, glucocorticoids, and azathioprine
   5. Excellent side effect profile with no increase in infections versus control
   6. Approved by FDA for prevention of acute renal allograft rejection
   7. Half life of the drug is ~20 days
   8. Dose is 1mg/kg over 15 minutes, given 24 hours before transplant and biweekly x 4
   9. Zenapax given during the three month induction period following cardiac transplantation reduced incidence of acute rejection 75% (from 63% to 18%) [19]
2. Basiliximab (Simulect®) [2]
   1. Chimeric IgG1 mouse Fab / human Fc monoclonal antibody
   2. Binds to anti-IL2R alpha chain (CD25) similar to daclizumab
   3. Used in combination with CsA, glucocorticoids and azathioprine
   4. Reduced acute rejection rate at 6 months from 44% to 30%
   5. Excellent side effect profile
   6. Approved by FDA for prevention of acute renal allograft rejection
   7. Half-life of the drug is ~7 days
   8. Dose is 20mg IV on day of transplantation and 20mg IV four days later

D. Tumor Necrosis Factor alpha Blockers [3]

1. Infliximab (anti-TNFa MAb, Remicade®) [4]
   1. Half life is 10 days when given intravenously
   2. 5-10mg/kg anti-TNFa Ab infusion usually produce significant improvement in symptoms
   3. Approved for use in severe Crohn's disease, especially to help heal fistulas
   4. In Crohn's Disease, responses usually occur at 2 weeks, last ~3 months
   5. Up to 68% of patients will heal 50% of their fistulas [5]
   6. Up to 55% of patients will heal all of their fistulas [5]
   7. Elevated TNFa levels predict acute relapse in Crohn's disease (consider therapy) [6]
   8. Well tolerated and effective therapy in ~50% of patients with refractory RA
   9. Overall well tolerated with nausea most common (17%)
   10. Serum sickness like symptoms reported in ~25% of Crohn's patients
2. Etanercept (Soluble TNFa Receptor, Enbrel®) [7,8]
   1. Soluble TNFa receptor absorbs and blocks TNFa biological activity
   2. This is not an antibody, but contains a human Fc IgG1 region
   3. Given as 10mg or 25mg sc injections twice weekly
   4. The 25mg sc dose has a half life of ~5 days
   5. Improves moderate and severe RA in 50-70% of patients
   6. May be used in combination with methotrexate and is synergistic
   7. Unclear if agent slows joint destruction
   8. Injection site reactions common, but no other major problems
   9. Drug is very effective and well tolerated in RA patients for >18 months
3. Adalimumab (Humira®) [42]
   1. Effective alone or in combination with MTX for moderate to severe RA
   2. Convenient dosing: 40mg sc every other week

E. Trastuzumab (Herceptin®) [11,40,43]

1. Anti-HER2/neu MAb blocks epidermal growth factor (EGF) receptor 2 (EGF-R2, also called human EGF receptor 2 (HER2) or Neu)
2. FDA approved for first line therapy of metastatic breast cancer
3. Effective in patients with amplification or overexpression of her2/neu
4. About 25% of patients with metastatic breast cancer overexpress her2/neu
5. May be used alone or in combination with paclitaxel
   1. Combination therapy with trastuzumab increased duration of median response from
6. 4 months to 13 months
   1. One year survival 68% with chemotherapy alone, 79% with chemotherapy + trastuzumab
7. Use as Adjuvant Therapy
   1. Studied in patients with node positive or negative breast cancer without other metastases
   2. One year of trastuzumab q3 weeks after at least 4 cycles of anthracycline chemotherapy in patients with HER2+ breast Ca reduced cancer related events by ~45% [44]
   3. One year of trastuzumab with paclitaxel both q3 weeks after doxorubicin-cyclophosphamide adjuvant therapy in HER2+ breast ca reduced disease progression and death 33% [45]
8. Cardiotroxicity [40]
   1. Clear increase in cardiotoxicity when used with athracyclines (27% of patients)
   2. Use alone in adjuvant setting reported cardiac problems in ~0.5% of cases [44]
   3. As monotherapy in metastatic disease, ~5% develop cardiac problems
   4. Combination with paclitaxel in adjuvant setting reported heart failure in 4% of cases [10]
   5. Overall cardiotoxicity with paclitaxel ~13%
9. Chills, fever, asthenia, pain, nausea occurred in 40% of persons at first infusion
10. About 25% of patients developed diarrhea
11. Some increase in infection rates with combination therapy
12. Should be used in all patients with HER2+ overexpression in adjuvant or metastatic setting

F. Anti-CD20 MAbs

1. CD20 is expressed on B lymphocytes, pre-B, but not pro-B lymphocytes
2. CD20 expressed on nearly all B cell non-Hodgkin's lymphoma (NHL) cells
3. Rituximab (Rituxan®) [12,20]
   1. IgG1 kapp chimeric mouse/human antibody which binds to CD20 antigen
   2. Nearly all low grade B cell NHL express CD20, as do normal B cells
   3. Rituximab depletes all CD20 expressing cells, including normal and malignant B cells
   4. Rituximab may also sensitize B cells to effects of some anticancer agents
   5. Given slowly IV once weekly (375mg/m2) for 4 weeks
   6. Median time to response was ~50 days
   7. Partial + complete responses with ribuximab alone occurred in ~50% of patients
   8. Combination of rituximab and chemotherapy (CHOP) produced very good overall responses
   9. Also show some efficacy in patients with intermediate and high grade NHL
   10. Adverse effects occurred with initial dose, usually an immediate hypersensitivity
   11. These effects respond to acetaminophen (Tylenol®) and diphenhydramine (Benadryl®)
   12. Activity in refractory autoimmune thrombocytopenia (ITP) but mortality 3% associated with use in ITP necessitates caution [10,17,18,19]
   13. Has also shown good efficacy alone or combined with cyclophosphamide or methotrexate in patients with methotrexate resistant RA; FDA approved in RA [48,49]
   14. Highly significant reductions in gadolinium lesions and volume with good tolerability in relapsing remitting multiple sclerosis (MS) [53]
   15. Consider use of ribuximab in relapsing MS (Phase III studies to be initiated)
4. 90-Yt Radiolabeled Anti-CD20 MAb (Bexxar®)
   1. FDA approved for rituximab refractory NHL
   2. Also approved for NHL following relapse after chemotherapy
   3. Requires initial dosing with "cold" (nonradioactive) anti-CD20 (rituximab)
   4. Some complete responses and many partial responses in rituximab refractory NHL
   5. Well tolerated with no acute side effects
   6. Thrombocytopenia was dose limiting
   7. Late radiation-related myelodysplastic syndrome and acute myeloid leukemia in <5%
5. I-131 Radiolabeled Anti-CD20 MAb (Zevalin®) [13]
   1. Labelled with I-131 increases efficacy considerably
   2. Unlabelled (non-radioactive) Ab showed 9% complete and 50% partial responses
   3. Radiolabelled Ab showed 50% complete and 79% partial responses
   4. With myeloablative levels of radiolabeled Ab, 79% complete and 86% partial responses

G. Cetuximab (Erbitux®) [28,29,30,33]

1. Chimeric mouse-human IgG1 MAb against ligand binding domain of epidermal growth factor (EGF) receptor 1 (EGF-R1)
2. EGF-R1 is upregulated in many cancers, particularly colorectal cancer (CRC)
3. CRC
   1. Partial responses to single agent 9-11%; 17-22% in combination with irinotecan in CRC [46]
   2. Side effects of cetuximab+irinotecan similar to irinotecan alone except for skin rash [47]
   3. In chemotherapy relapsed patients, cetuximab improve overall survival 6.1 months versus
4. 6 months with best supportive care [51]
   1. Efficacy not affected by type of prior chemotherapy
5. Enhances cytotoxic effects of radiation in squamous cell cancer SCC (head and neck)
6. In combination with high-dose radiotherapy, improved progression free and overall survival in patients with locoregionally advanced head and neck SCC [30]
7. Side Effects
   1. Acne-like skin rash in up to 88% of patients, severe in 12%
   2. Severe hypersensitivity reactions occur in >3% (or more), higher rates in southern USA [54]
   3. Most patients with hypersensitivity to cetuximab have IgE Abs specific for cetuximab and to the disaccharide galactose-alpha-1,3-galactose [54]
8. Loading dose of cetuximab 400mg/m2 IV over hours, then 250mg/m2 over 1 hour weekly
   1. Pretreatment with diphenhydramine (Benadryl®, others) to reduce infusion reactions
   2. Infusion reactions severe ~3% with first infusion (do not retreat after severe reaction)
   3. For mild or moderate infusion reactions, reduce rate of infusion 50%
9. Also being evaluated in head and neck cancer, pancreatic and lung cancers

H. Panitumumab (Vectibix®) [38]

1. Anti-EGF-R mAb (IgG2) approved for recurrent CRC
2. No benefit (possible harm) in combination with first line therapy
3. Improved mean PFS to 96 days from 60 days with best supportive care
4. Dose is 6mg/kg IV over 60 minutes q14 days

I. Anti-alpha4 Integrin MAb (natalizumab, Tysabri®) [21,24,39]

1. Humanized MAb to alpha4-beta1 (a4b1) and alpha4-beta7 (a4b7) integrins
   1. Blocks association of a4b1 (also called VLA-4) with VCAM-1 and CS-1
   2. Blocks association of a4b7 (also called LPA-1) with MadCAM-1 and VCAM-1
2. Multiple Sclerosis [22,39]
   1. Lymphocytes and monocytes express a4b1 integrin
   2. Six-month randomized study of monthly natalizumab in relapsing multiple sclerosis
   3. Reduced new MRI lesions by >90%
   4. Reduced clinical relapses by 50% during 6 months of treatment
   5. Adverse events similar to placebo except for emerging PML risk
   6. Rare cases of PML (progressive multifocal leukoencephalopathy) reported [25,26,27]
   7. Do not use in combination with other immunosuppressive agents
   8. Appears to be most potent treatment for multiple sclerosis (MS)
3. Crohn's Disease [23]
   1. Lymphocytes homing to the gut express a4b7 integrin
   2. One to two infusions given to patients with active Crohn's Disease (CDAI 220-450)
   3. Some effect of higher dose natalizumab in inducing remissions
   4. Natalizumab also improved quality of life and reduced C reactive protein
   5. Adverse effects similar to placebo except for PML risk

J. Anti-CD52 (alemtuzumab, Campath®)

1. CD52 is expressed on most lymphocytes
2. Effectively lysis malignant lymphocytes
3. Also causes T and B cell depletion from blood
4. Effective in resistant chronic lymphocytic leukemia (CLL)
5. Pneumocystis and cytomegalovirus prophylaxis required during use

K. Anti-CD33 MAb (gemtuzumab, Mylotarg®) [16]

1. CD33 expressed on majority of myeloid lineage cells
2. Gemtuzumab is recombinant human MAb to CD33 linked to calicheamcin toxin
   1. CD33 expressed on leukemic blasts in >80% of patients
   2. Calicheamicin is released in lysosomes of target cell and binds to DNA minor groove
3. FDA approved for treatment of CD33+ acute myeloid leukemia in first relapse
4. Usually give two doses, 14 days apart
5. Complete remission occurs in ~30% of patients given gemtuzumab
6. Some acute cytokine release symptoms occur within 4 hours of dosing
7. Nearly all patients develop severe neutropenia and thrombocytopenia

L. Tocilizumab [56,57]

1. Humanized mAb binds both cell-bound and soluble forms of interleukin 6 (IL6) receptor
2. RA patients on Methotrexate with Suboptimal Responses [56]
   1. Doses 4-8mg/kg IV q4 weeks for 24 weeks
   2. At 24 weeks, ACR50 in >40% at 8mg/kg versus >10% on placebo
   3. At 24 weeks, ACR20 in >55% at 8mg/kg versus >20% on placebo
   4. Serious adverse events in 3% at 8mg/kg, 1.5% at 4mg/kg, 1% on placebo
   5. Otherwise, generally well tolerated
3. Systemic-Onset Juvenile Chronic Arthritis (Still's Disease; Systemic Onset JCA) [57]
   1. Dose 8mg/kg IV q2 weeks x 6 weeks, then randomized to placebo or drug for 12 weeks
   2. After week 18, 80% of tocilizumab and 17% of placebo maintained ACR Pedi 30 responses
   3. Generally well tolerated, with minimal anaphylactoid and other serious adverse events
   4. May be reasonable treatment for systemic onset JCA

M. Omalizumab (Xolair®) [31,32]

1. Recombinant humanized monoclonal anti-human IgE antibody developed
   1. Recognizes human IgE specifically at the same part of Fc region as the Fc(E) receptor
   2. Reduces serum concentrations of free IgE immediately after one injection
   3. Total serum IgE levels increase after administration due to immune complex formation
2. Attenuates early- and late-phase reactions to inhaled allergens
3. FDA approved for used in persistent asthmatics with elevated serum IgE levels
   1. Biweekly IV dosing for 20 weeks in adults with allergic asthma on some form of glucocorticoids led to improved asthma scores and reduced need for glucocorticoids
   2. Some reduction in daily ß-adrenergic agonist use seen in treated patients
   3. Serum IgE levels were reduced >95% with high and low dose anti-IgE treatments
   4. Subcutaneous dosing every 2-4 weeks for 16 weeks in children with allergic asthma reduced inhaled glucocorticoid use and asthma exacerbations
4. Side Effects
   1. Antibodies to the anti-IgE treatments developed in all patients
   2. Side effects were not different in placebo versus treated patients
   3. Anaphylaxis in ~0.2% of patients, typically within 2 hours after first dose if it occurs [50]
5. Total serum IgE level should be measured in all patients prior to omalizumab

N. Bevacizumab (anti-VEGF MAb, Avastin®) [33,34,41,58]

1. Antibody (Ab) to vascular endothelial growth factor (VEGF)
2. Humanized monoclonal Ab (MAb) with efficacy in multiple cancers
3. FDA Approved Indications [9]
   1. Metastatic colorectal cancer - first line in combination
   2. Metastatic non-small cell lung cancer
   3. Metastatic breast cancer - first line with paclitaxel (Taxol®) in HER2 negative disease
   4. Activity in other cancers (see below)
4. Bevacizumab with irinotecan+5FU/LV increases survival versus chemotherapy alone as initial CRC treatment: 20.3 versus 15.6 months [28]
5. Bevacizumab added to paclitaxel+carboplatin increased survival in Stage IIIB/IV non-small cell (non-squamous) lung cancer from 10.3 to 12.3 months [60]
6. In Stage IV breast cancer, bevacizumab plus paclitaxel improved progression-free survival versus paclitaxel alone (11.8 and 5.9 months); similar overall survival (~26 months) [9,52]
7. Activity in renal-cell carcinoma and in previously untreated pancreatic carcinoma
8. Used "off-label" for wet form of age-related macular degeneration (ARMD)
9. Side Effects
   1. Gastrointestinal bleeding or performation 2% in clinical trials
   2. Hypertension; uncommon hypertensive crisis, renal dysfunction, proteinuria
   3. Severe, sometimes fatal pulmonary hemorrhage in lung cancer patients
   4. Epistaxis, thrombosis, asthenia uncommon
10. Delay therapy for 28 days after major surgery; avoid prior to elective surgery
11. Systemic dose is 5-10mg/kg every 2 weeks or 15mg/kg every 3 weeks IV [9]
    1. First dose 90 minute infusion
    2. Second infusion over 60 minutes if well tolerated
    3. Subsequent doses over 30 minutes if well tolerated

O. Ranibizumab (Lucentis®) [35,36]

1. Monoclonal anti-VEGF Ab fragment
2. Most effective therapy currently available
3. Superior to verteporfin
4. Intravitreal injection of 0.3mg or 0.5mg monthly for at least 1 year
5. Serious adverse effects: endophthalmitis (1.4%), uveitis (0.7%)

P. Ustekinumab (anti-p40 mAb)

1. mAb to p40 protein, which is a subunit of both IL12 and IL23 (Th1 cytokines)
2. In phase II, single doses and 4 once weekly doses of 45mg or 90mg of ustekinumb significantly improved moderate-severe plaque psoriasis with good tolerability [59]
3. Responses in phase II were sustained at 12, 16, and 20 weeks after single doses
4. In a 12 week trial, ustekinumab subcutaneously 45mg or 90mg at weeks 0 and 4 lead to PASI 75 in 66-75% versus placebo <4% [60,61]
5. Responses to ustekinumab are durable for up to 76 weeks after intermittent dosing [30]
6. Very well tolerated with this regimen, with serious adverse events similar to placebo

Q. Anti-RSV MAb (palivizumab, Synagis®)

1. Humanized MAb against respiratory syncytial virus
2. Treatment of infants at high risk for RSV:
   1. Premature infants
   2. Infants with bronchopulmonary dysplasia (BPD)
3. Dose is 15mg/kg
4. Reduced RSV infections by >50%
5. Very well tolerated 6. FDA approved for wet AMD

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