PHC 502: Drug Development

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Biological Drugs
PHC 502 Drug Development
Dr. Ruitang Deng
Wednesday, October 4, 2006
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Input and Output on Drug Development During the
previous 10 years
Input Increase
Output Decrease
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Characteristics of Biological vs Pharmaceutic
Drugs
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Types of Biological Drugs

• Vaccines Preventive and therapeutic
• Antibodies Therapeutic
• Other Proteins Therapeutic
• Hormones Growth hormone, estrogen
• Plasma proteins albumin, plasminogen activator
• Enzymes urokinase
• Cytokines TNF, IL-2, IL-10, G-CSF
• Others Interferon, Insulin, erythropoietin
  (Epo)
• FORMS
• Proteins Preventive and therapeutic
• DNA Gene therapy, Cancer
• RNA Cancer, CVD, CNS
• Peptides Cancer, CNS

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Immunobiologics

• Immunobiologics any components in immune-related
  responses, and can be used to treat or prevent
  diseases.
• Vaccine is one type of immunobiologics
• Additional common immunobiologics include
  antibody, antibody derivatives, cytokines,
  interferon (IFN), complements, immune cells and
  their components.

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Vaccine vs Toxoid

• Toxoid a toxin which has been modified so that
  it is no longer toxic, but which retains its
  antigenic functions. Can be used as a vaccine
  either alone, or in combination with anti-toxin
  molecules.
• Toxoid is a type of vaccine
• Common toxoids botulinum, diphtheria, and
  tetanus toxiod

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Most Recently Approved Vaccine by FDA
Preventive vaccine for cancer
Proper name Quadrivalent Human Papillomavirus
(Types 6, 11, 16, 18).
Recombinant Vaccine Tradename
GARDASIL Manufacturer Merck Co., Inc., West
Point, PA, License 0002 Indication for Use
Vaccination in females 9 to 26 years of age for
prevention of the following
diseases caused by Human
Papillomavirus (HPV) Types 6, 11, 16, and 18
(1) Cervical cancer (2) Genital warts
(condyloma acuminata) Approval Date
6/8/2006 Type of submission Biologics license
application STN 125126/0
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An Successful Story of Vaccination
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Requirements for an Effective Vaccine

• Must be safe
• Produce protective immunity
• Long-lasting
• Cost-effective
• Easy to be distributed
• Easy to be administrated

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Innate vs Acquired Immunity (Vaccination)

• Innate
• Early phase
• Non-specific
• No memory
• Complement
• Cytokines
• Acute phase proteins
• Macrophages
• Neutrophils

• Acquired
• Later phase
• Antigen-specific
  
• memory
• Antibodies
• Cytokines
• T cells
• B cells

Characteristics
Humoral
Cellular
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Humoral vs Cellular Immunity
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Primary vs Secondary Response
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Types of Vaccines

• Currently available
• Live attenuated vaccines
• Killed vaccines
• Subunit vaccines
• Recombinant vaccines
• Currently under research and development
• Synthetic peptide or epitope vaccines
• Genetic vaccines
• Vectored vaccines
• Edible vaccines

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Live Attenuated Vaccines

• Approaches
• Serial passages in vitro or in vivo
• Host range mutants
• Isolation of naturally attenuated pathogens
• Isolation of conditional or TM sensitive mutants
• Genetic modification

• Characteristics
• Capable of replicating
• Do not cause disease
• Induce strong immune responses
• Long duration (Single dose)

• Safety Concerns
• Reversion to wild type
• Cause disease in immunodefficient individuals
• Potential recombination with wt pathogens
• Hyposensitivity reaction

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Killed Vaccines

• Characteristics
• Not capable of replicating
• Do not cause disease
• Induce relatively weak immune responses
• Shorter duration (Multiple doses)

• Safety Concerns
• Vaccine not completely killed
• Contamination
• Hypersensitivity

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Subunit Vaccines

• Approaches
• Grow the pathogens
• killed the pathogens
• Purify the vaccine subunits
• Formulate the vaccine

• Characteristics
• A component of pathogen included
• Do not cause disease
• Induce weak immune responses
• Shorter duration (Multiple doses)
• Conjugated or Adjuvanted to achieve efficacy
• Safety Concerns
• Hypersensitivity

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Recombinant Vaccines

• Approaches
• Molecular clone the antigen gene
• Expression and production of the antigen
• Isolation and purification of the antigen
• Formulation of the vaccine

• Characteristics
• Single component of pathogen included
• Do not cause disease
• Using recombinant technologies
• Induce weak immune responses
• Shorter duration (Multiple doses)
• Conjugated or adjuvanted to achieve efficacy
• Safety Concerns
• Best safety profile

Hepatitis B Viral Surface Antigen (HBs-Ag)
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Synthetic Peptide or Epitope Vaccines
Characteristics

• Combination of multiple peptides
• Cost-effective
• Good safety profile
• Efficacy?

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Genetic (DNA)Vaccines

• Easy to be produced
• Cost-effective
• Induces humoral and cellular immunity
• Combination of multiple antigens
• Low delivery efficiency/efficacy?
• Safety concerns
• Integration

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Vectored Vaccines
Attenuated or non-pathogenic viruses or bacteria
as vaccine carriers

• Capable of replicating
• Do not cause disease
• Induce stronger immune responses
• Longer duration
• Safety concerns
• Reversion
• Recombination

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Edible Vaccines

• Easy to be produced
• No injection, no needle
• Easy to be stored
• No training for administration
• Even taste good
• Cost-effective
• Good safety profile
• Efficacy?

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Challenges and Opportunities
Opportunities

• Whole genome sequenced for many pathogens
• Novel virulent gene identified
• More understanding of pathogen-host interaction
• New Technologies available

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Challenges and Opportunities
Challenges

• Pathogens
• Host range jump e.g. Influenza virus
• Attack immune system e.g. HIV
• Persistent or latent infection e.g. HCV, HPV
• Constant mutation RNA viruses

• Technologies
• Delivery techniques
• Immune enhancer

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Therapeutic Vaccines

• In the infant stage
• A few products in the market (3)
• Majority in the preclinical and clinical stage
  (85)
• Modulate host immune responses enhance or
  suppress
• Similar technologies used as in making
  preventive vaccines

• Types of Vaccines
• Protein/Adjuvant Vaccines
• DNA and Viral Vector Vaccines
• Peptide Vaccines
• Oncolytic Virus Vaccines
• Whole Cell Tumor Vaccines
• Dendritic Cell Vaccines (DCs)

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Targets of Therapeutic Vaccines
Chronic viral infection HIV, HCV, HBV and
HPV Cancer Prostate cancer vaccines - pox
virus vaccines carrying prostate-specific antigen
(PSA) Melanoma vaccine - DNA vaccine containing
the human gene for HLA-B7) Lung cancer -
modified tumor cells as antigens Cervical cancer
anti-HPV Drug addition cocaine and nicotine,
antibody against drugs Allergy and autoimmune
diseases T cell epitopes (peptide) vaccine to
desensitize Others CNS and CVD
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Therapeutic Cancer Vaccines on the Market
OncoVax (Intracel) colon cancer in EU market,
modified tumor cells with G-CSF M-Vax (AVAX
Tech.) stage III melanoma in EU market, hapten
dinitrophenyl (DNP) modified tumor
cells Melacine (Corixa) Stage IV melanoma in EU
market, mixed two lysated tumor cell lines plus
adjuvant
The first in US market Gardasil (Merck)
cervical cancer, a combined human papillomavirus
vaccine
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Cancer Vaccines in Development
MUC1 Vaccine Multivalent Antigen
Vaccine MVA-HPV-IL2 Vaccine MVA-MUC1-IL2
Vaccine Mylovenge MyVax Personalized
Immunotherapy Norelin Oncophage OncoVax Onyvax-P P
anVac-VF Patient-specific Vaccines Prostate
Cancer Vaccines ProstVac-VF Provenge TA-HPV/TA-CIN
TVAX Telomerase Therapeutic Vaccine
GnRH Pharmaccine GVAX Vaccines GVAX Leukemia
Vaccine GVAX Lung Cancer Vaccine GVAX Myeloma
Vaccine GVAX Pancreatic Cancer Vaccine GVAX
Prostate Cancer Vaccine IGN101 Insegia Insegia
(Continued) Lung Cancer Vaccines M-Vax MAGE-12
170-178 Peptide Vaccine MART-1/Melan-A MDX-1379 Me
lacine MUC1 Vaccine
AG-858 Allovectin-7 Alvac-CEA/B7.1 Avicine BEC2 Bi
ovaxid BLP25 Canvaxin CeaVac Cervarix CG7870 Colli
dem Colorectal Cancer Vaccine DCVax-Brain Eladem E
P-2101 FavId GMK
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Some Concepts in Cancer Vaccines
Autologous vs Allogenic
Personalized vs Generalized Vaccines
In Vivo vs Ex Vivo Vaccines
Monovalent vs Combination Vaccines
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Therapeutic Antibodies

• In a fast growing stage
• More than nineteen therapeutic Abs have been
  approved
• World wide sale reaches 12 billions in 2005
• More than 370 programs currently in the
  pipeline
• Highly specific
• Short duration for development
• Polyclonal or monoclonal
• Major side effect the antigenecity of the Ab

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Strategies and Production

• Direct against the target gene function
• Conjugated with small molecule drugs, toxins,
  or radioactive payloads
• Fused with therapeutic molecules
• Fragment of Ab increasing intracellular
  entering

• Production
• Polyclonal antibodies antiserum from
  vaccinated host
• Monoclonal antibodies hybridoma cells
  producing mAB
• Recombinant antibodies recombinant technology

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Trends in Therapeutic Ab Development
Polyclonal Antibodies
Marine monoclonal antibodies
Chimeric antibodies
Humanized antibodies
Fully human antibodies
Fully polyclonal human antibodies
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The Structure of Antibodies
CDRs Complementarity-Determining Regions FRs
Framwork Residues
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Polyclonal Therapeutic Antibodies
Animal derived
Human derived
Healthy human donor
Vaccination of animals
Collect serum
Animal
Purification of IgG
No side-effect Repeat administration Limited
sources Non-specific
Side-effect Anti-IgG response Large sources More
specific
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Murine Monoclonal Antibody (mAb)
Naturally occurring Specific Side-effect Lower
productivity
Technology (1975) First mAb drug (1983)
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Chimeric Monoclonal Antibody (cmAb)
Recombinant 75 human sequences 25 murine
sequences Specific Less side-effect Easy
production Anti-Ab observed
Recombinant Ab Technology (1984) First cmAb drug
(1994)
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Humanized Monoclonal Antibodies (hmAb)
CDR
FR
Recombinant 95 human sequences 5 murine
sequences Specific Less side-effect Easy
production Less-potent?
Murine
Human
Technology (1986) First hmAb drug (1997)
Humanized
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Fully Human Monoclonal Antibodies (hmAb)
Conventional hybridoma technology
New Technologies
Libraries establishment and phage display
Difficulty if not impossible

• Human hybridoma and immortalized
• cell lines do not stably product Ab
• In vivo immunization of human is not
• feasible for many antigens
• Hard to produce anti-self immune response

Transgenic mice
Recombinant 100 human sequences Specific Less
side-effect
Technology (1998) First hmAb (2002)
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Humanized Mice to Produce Human Abs
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Fragments of Antibodies as Therapeutics

• Easier penetration in tissues
• Better clearance
• Easier to produce
• Affinity may compromised

Fab antigen-binding fragment Fv variable
fragment scFv single-chain Fv dsFv
disulfate-stabilized Fv
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Challenges for Biological Drugs
Production
Delivery
Delivery
Production
Production
Delivery
Injection Oral Particles Polymers
Cell Culture Eggs Plants Animals