Mabs

1. Therapeutic monoclonal antibodies
-Why they are becoming so common
-Some perspectives for internal medicine
BRIAN SKAUG
RESIDENT UPDATE TALK
MARCH 2ND-3RD 2015

2. Most internal medicine specialties have monoclonal antibodies at their disposal
Hematology/Oncology: rituximab (Rituxan), bevacizumab (Avastin), many more
Rheumatology: infliximab (Remicade), adalimumab (Humira), many more
Gastroenterology: Remicade, Humira
Endocrinology: denosumab (Prolia)
Cardiology: abciximab (ReoPro), PCSK9 inhibitors soon
Allergy/Pulmonary: Omalizumab (Xolair)
Nephrology: basilixumab for certain transplant recipients
Also Dermatology (Humira, others), Ophthalmology (Avastin), Neurology (natalizumab/Tysabri)

3. Production of therapeutic monoclonal antibodies is rapidly increasing
Year: 1986 2000 2015 2025
Number of FDA-approved mAb’s
1 6 ?36
39 mAb’s currently in
Phase 3 clinical trials
Muromonab
(OKT3) for renal
transplant
patients
http://www.antibodysociety.org/news/approved_mabs.php
http://www.antibodysociety.org/news/news_mnth.php

4. Clinical and basic science advances that led to therapeutic mAb production
1890’s: von Behring: serum therapy to treat diphtheria.
First demonstration of
therapeutic passive immunity
Passive
immunity
1890’s
In vitro
mAb’s
1975
-Structure/function
of DNA
-Genetic code
-Structure of Ab’s
1940’s-60’s
-recombinant DNA
technology
-Transgenic and
knockout mice
-genetics of Ab
diversity
1980’s 1990’s
-Genomics
-Proteomics
-better understanding of
disease pathophysiology
-identification of numerous
drug “targets”
-understanding of antibody
structure/function
-use of non-human vectors
(mice, bacteria) to mass
produce pre-specified
proteins or antibodies

5. 1975: Isolation of monoclonal antibodies using hybridoma technology
1975: Kohler and Milstein--fused mouse
lymphocytes with immortalized cells to
produce monoclonal antibodies in vitro

6. 1986: Muromonab/OKT3—the first therapeutic monoclonal antibody
The good:
some benefit in patients with acute
transplant rejection
The bad:
vast majority of patients develop antibodies
against muromonab—reduced half-life and
diminished response on repeat injections
N Engl J Med. 1992 Sep 3;327(10):736.
Anaphylactic shock after retreatment with OKT3 monoclonal
antibody.
Abramowicz D, Crusiaux A, Goldman M.
The ugly:
Reviewed in Weiner, J Immunther. 2006

7. Conversion of mAb’s from mouse to partially or fully human was the
final step to effective and safe therapeutic mAb’s
Rituximab (Rituxan)
Infliximab (Remicade)
Human constant
domain + rodent
variable domain
Trastuzumab (Herceptin)
Bevacizumab (Avastin)
Rodent
complimentarity-
determining region
-Human immunoglobulin
genes in mouse
-Phage display (in vitro)
Adalimumab (Humira)
Denosumab (Prolia)
Images adapted from Foltz et al.
Circulation. 2013

8. Phage display and transgenic mice:
Two different methods to produce
human mAb’s
Nelson et al., Nat Rev Drug Disc. 2010 Brekke et al., Nat Rev Drug Disc. 2003

9. 2003: PCSK9 mutations identified as a cause of autosomal dominant hypercholesterolemia.
Abifadel et al., Nat Gen. 2003
PCSK9 inhibitors—from target identification to therapy in a decade
2003-2006:
identification and
characterization of
target
2009:
mAb produced and
studied in animals
2011-2014:
Human trials
applications for FDA approval
2004: Mouse studies show PCSK9 downregulates LDL
receptor, raising serum LDL
Maxwell et al., Proc. Natl. Acad. Sci., 2004
Park et al., J. Biol. Chem. 2004
Benjannet et al., J. Biol. Chem. 2004
Image adapted from Mullard., Nat Rev Drug Disc. 2012
2005: loss of function mutations in
PCSK9 are associated with low LDL
Cohen et al., Nat Gen. 2005
And…
2006: reduced risk of coronary heart disease
Cohen et al., NEJM. 2006
2014: 3 different mAbs against PCSK9
being tested in phase 3 clinical trials
Dadu et al., Nat Rev Cardiol. 2014
2009: Animal study using monoclonal
antibody targeting PCSK9
Result: reduced LDL levels
Chan et al., Proc Natl Acad Sci. 2004
2012: Numerous phase 2 trials show
LDL reduction by anti-PCSK9 mAb’s
Dias et al. J Am Coll Cardiol. 2012
Koren et al. Lancet. 2012
Guigliano et al. Lancet. 2012
Raal et al., Circulation. 2012
Sullivan et al., JAMA. 2012
McKenney et al., J Am Coll Cardiol. 2012
Stein et al., NEJM. 2012
Stein et al., Lancet. 2012
Roth et al., NEJM. 2012
Image from Stein et al., NEJM. 2012

10. Therapeutic monoclonal antibodies are costly
Annual cost, Medicaid population
Bonafede et al., Clinicoecon Outcomes Res. 2014
Estimated costs based on
Uptodate.com
Herceptin $4460 $70,000
Avastin $3,000 variable
Remicade $2,200 $20,000
Prolia $1,100 $2,200
Single dose Annual

11. Several commercial factors favor reliance on mAb’s for future therapies
-mAb’s are profitable
-numerous companies now have “infrastructure” for mAb
development
◦ >15 companies with FDA-approved mAb’s
-mAb’s are more likely to “succeed”
◦ 14% likelihood of mAbs in phase 1 getting FDA approval
◦ 7% likelihood of small molecules
-No such thing as a “generic” mAb
2011 US sales data (in billions)
Aggarwal. Nat Biotechnol. 2012
http://www.actip.org/pages/monoclonal_antibodiestable.html
Hey et al., Nat Biotechnol. 2014

12. Lessons from TNFa inhibitors:
proven benefits, diminishing responses, and unanticipated adverse effects
1997: Infliximab effective in refractory
Crohn’s Disease
Targan et al., NEJM. 1997
TNFa inhibitors are currently FDA approved for:
-Crohn's disease, ulcerative colitis
-Rheumatoid arthritis
-Ankylosing spondylitis
-Psoriatic arthritis
-Plaque psoriasis
http://www.drugs.com
2003: Anti-infliximab antibodies,
infusion reactions, and loss of
treatment response
Baert et al., NEJM. 2003
2009: Adalimumab (human) has lower
but still large percentage of anti-mAb
Ab formation and treatment failure
compared to infliximab in RA patients
Radstake et al., Ann Rheum Dis. 2009
Increased risk of TB reactivation in RA patients treated
with infliximab (24 per 100,000 vs 6 per 100,000)
Keane et al., NEJM. 2001
Worsening of CHF by infliximab
Chung et al., Circulation. 2003
Alternative therapy regimen without biologic
has similar longterm efficacy for RA.
van Vollenhoven et al. Lancet. 2012
Roughly 17,000 euro difference in cost at
21 month follow up.
Eriksson et al., Ann Rheum Dis. 2014
Large percentage of Crohn’s Disease
patients have diminishing response to
TNFa inhibitors.
Ben-Horin et al., Ailment Pharmacol
Ther. 2011

13. Some perspectives for Internal Medicine
-Lots of mAb’s already available, many more on the way
-Potential for meeting some unmet medical needs
-Universally expensive
-Diminishing therapeutic response is a problem even with human mAbs
-Require same stringency for safety, efficacy, and cost-effectiveness as “traditional” drugs

14. Coming soon to a clinic near you…
Monoclonal antibodies approved by the FDA in 2014
Name of mAb Molecular target Disease it is approved for
Siltuximab Interleukin-6 Castleman Disease
Vedolizumab a4b7 integrin inflammatory bowel disease
Ramucirumab VEGFR2 gastric cancer
Pembrolizumab PD1 melanoma
Blinatumomab CD19,CD3 acute lymphoblastic leukemia
Nivolumab PD1 melanoma
http://www.antibodysociety.org/news/approved_mabs.php