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Biological Response Modifiers

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Title: Biological Response Modifiers


1
Biological Response Modifiers
  • Endogenous proteins stimulate the formation of
    blood cells during hematopoiesis
  • Through rDNA, possible to produce quantities
    necessary to treat patients
  • Reduce infections in patients with AIDS,
    infectious diseases and cancer chemotherapy

2
The Hematopoietic Cascade
Lymphoid
Myeloid
Granulocytes
3
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4
Life Span of Blood Cells
  • Erythrocyte 120 days
  • Platelet 7-10 days
  • Monocyte 3 days
  • Neutrophil 7-12 hours
  • Lymphocyte 3 months to 10 years

5
Role of Hematopoietic Growth Factors
  • Regulates the proliferation and differentiation
    of progenitor cells.
  • Proliferation (reproduction of similar cells)
  • Differentiation (acquisition of function)
  • Mobilize progenitor cells to move from bone
    marrow to peripheral blood.
  • Regulates the survival and function of mature
    hematopoietic cells.

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7
Hematopoietic Cell Growth Factors
Soluble mediators that aid communication between
cells (primarily immunological, hematological,
neurological) Glycoproteins 60 different
cytokines Targeted to produce local
effects Brief, self-limiting effect
8
Hematopoietc Cell Growth Factors
Erythropoietin Colony stimulating factors (G-CSF,
etc.) Interleukins Interferons Chemokines
9
Pluripotent Stem Cell
  • Most primitive blood-forming cell.
  • All blood cells develop from this master cell.
  • Located primarily in bone marrow (some in blood
    spleen).

10
Approved Biological Products Growth Factors
Generic Name Brand Name Company Therapeutic
Area (1st Date of Approval) Epoetin
alfa EPOGEN (Amgen) Certain anemias from
chronic renal disease (1989) Procrit
(Ortho Biotech) Zidovudine-induced anemia
(1991) cancer (1993) Anemia in
chemotherapy(1993) surgery patients
(1996) Filgrastim NEUPOGEN
(Amgen) Neutropenias due to myelosuppressive
(r-metHuG-CSF) chemotherapy (1991) Myeloid
reconstitution after bone marrow
transplantation (1994) Severe chronic
neutropenia (1994) Peripheral blood
progenitor cell transplant (1995) Induction
and consolidation therapy in AML (1998)
Sargramostim Leukine (Berlex) Myeloid
reconstitution after bone marrow
(GM-CSF) transplantation (1991) Bone marrow
transplant failure (1994) Adjunct to
chemotherapy in AML (1995) Peripheral blood
progenitor cell transplant (1995) Darbepoetin
alfa Aranesp (Amgen) Anemia associated with end
stage renal disease and (NESP) chronic renal
insufficiency (2001) cancer (2002) Becaplermin
(PDGF) Regranex (Ortho-McNeil) Diabetic foot
ulcer (1997) Pegfilgrastim Neulasta (Amgen) Neu
tropenias and infections due to
myelosuppressive chemotherapy (2002)
11
Role of hematopoietic growth factors in
erythrocyte formation
12
Erythropoietin
  • Endogenous glycoprotein, produced in kidneys.
  • Promotes survival stimulates division/differentia
    tion RBC precursors in bone marrow.

13
Epogen Procrit
  • Recombinant human erythropoietin
  • Glycosylated protein
  • Same biological activity as endogenous
    erythropoietin
  • Anemia associated with
  • Chronic renal failure
  • AZT-treated HIV patients
  • Cancer patients on chemotherapy
  • Surgeries (noncardiac, nonvascular) some blood
    loss, reduce need for blood transfusions.

14
Aranesp (darbopoetin alpha)
Modified recombinant erythropoietin Engineered
for additional glycosylation sites Increased
serum half life
15
GM-CSF and G-CSF Stimulate Hematopoietic Cells
GM-CSF and G-CSF
  • Sargramostim (GM-CSF), Leukine (Berlex)
    Stimulates granulocytes (mostly
    neutrophils) monocytes
  • Filgrastim (G-CSF), Neupogen (Amgen)
  • Stimulates granulocytes (mostly neutrophils)
  • Pegfilgrastim (G-CSF), NeulastaTM (Amgen)

16
The role of GM-CSF versus G-CSF
GM-CSF
G-CSF
GM-CSF
GM-CSF
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18
GM-CSF (Sargramostim) Broad Acting Factor
  • Complementary activity with G-CSF
  • Involved in activating neutrophil production
  • Enhances neutrophil chemotaxis and serum half
    life
  • Stimulates macrophage production

19
Sargramostim (GM-CSF) approved indications
  • Chemotherapy induced neutropenia in patients with
    acute myelogenous leukemia (AML).
  • Mobilization of stem cells following stem cell
    transplantation.
  • Myeloid recovery following autologous bone
    marrow transplantation.
  • Myeloid recovery allogeneic bone marrow
    transplantation.
  • Bone marrow transplantation failure.

20
G-CSF (Filgrastim)
  • Involved in maintaining neutrophil production and
    in increasing production during infection or
    other stimulation.
  • Targets granulocytes, mostly neutrophils.

21
Filgrastim (G-CSF) approved indications
  • Cancer patients receiving myelosuppressive
    chemotherapy.
  • Cancer patients receiving bone marrow
    transplantation.
  • Patients undergoing peripheral stem cell
    harvesting.
  • Severe chronic neutropenia.
  • Prevention of infection in AIDS patients.

22
G-CSF/GM-CSF are used to treat infections
  • Neutropenia secondary to chemo/radiation therapy
  • Bone marrow transplantation
  • Infectious disease

23
Neutropenia from chemo/radiation therapy
  • Neutrophils are the shortest-lived blood cells
  • (7-12hrs).
  • Most susceptible to toxicity from therapy.
  • Both G- and GM-CSF stimulate neutrophil
    production.

24
Advantages of G-CSF/GM-CSF in chemo-induced
neutropenia
  • Reduce infections secondary to the toxic therapy
  • Allow for dosage escalation of chemo/radiation
  • kill more of the cancer

25
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26
Use of G-CSF/GM-CSF in Bone Marrow
Transplantation (BMT)
  • Goal of BMT is to obtain stem cells from the bone
    marrow.
  • 1 stem cell per 100,000 bone marrow cells.

27
Bone marrow may be damaged by
  • Aplastic anemia (too few stem cells produced)
  • Leukemia (defective or immature blood cells
    produced)
  • Immune-deficiency disease
  • Chemo/radiation therapy

28
Autologous BMT
  • Patient receiving their own bone marrow
  • Most common type of BMT
  • (21 compared to allogeneic)

29
Autologous Bone Marrow Transplant
Bone marrow may be purged to remove cancer cells
Bone marrow frozen
Bone marrow harvested from Patient
Bone marrow thawed
Patient
Bone marrow reinfused
High-dose chemotherapy and/or radiation
30
Allogeneic BMT
  • Patient receives marrow from a donor
  • Donors tissue should match recipients (family
    member)
  • Risk of graft versus host disease (GVHD)
  • donors marrow (graft) attacks patient (host)

31
Allogeneic Bone Marrow Transplant
Bone marrow harvested from donor
12-24 h
Patient
chemotherapy and/or radiation
Bone marrow transplant
Medication to prevent graft-versus-host disease
32
Peripheral stem-cell harvest
Patient undergoing peripheral stem-cell harvest.
33
Peripheral stem-cell harvest
  • Method of harvesting stem cells from the
    circulating blood cells
  • Patient is connected to an apheresis machine
    which separates blood cells
  • Stem cells collected
  • Other blood cells are returned to patient

34
CSFs and BMT
  • Harvested stem cells are given to patient
  • Several weeks following BMT, the transplanted
    marrow must graft and proliferate
  • During this period the patient is susceptible to
    infection
  • CSFs are beneficial during this period

35
Advantages of CSFs
  • Benign side-effect profile
  • Potential broad applicability over a wide range
    of disorders

36
Approved Biological ProductsBlood Factors
Cytokines
  • Generic Name Brand Name Company Therapeutic
    Area (1st Date of Approval)
  • Aldesleukin (IL-2) Proleukin (Chiron) Metastatic
    renal cell carcinoma (1992) Metastatic
    melanoma (1997)
  • Oprelvekin (IL-11) Neumega (Genetics
    Institute)Thrombocytopenia with chemo (1997)
  • Denileukin diftitox Ontak (Ligand) Cutaneous
    T-cell lymphoma (1999)
  • Factor 8 Kogenate (Bayer) Hemophilia A (1992)
  • Recombinate (Baxter) Bioclate
    (Baxter) (1993)
  • ReFacto (Genetics Institute)
  • Helixate FS (Aventis Behring)(1994, 2000)
  • Advate (Baxter) (2003)
  • Factor 7 NovoSeven (Novo Nordisk) Hemophilia
    (F.7 deficiency) (1999)
  • Factor 9 BeneFIX (Genetics Institute) Hemophilia
    B (1996)
  • Factor 8 Humate-P (Aventis Behring)Von
    Willebrands disease (1999)
  • von Willebrand Factor

37
Interleukins
  • IL-1 --- IL-18
  • Varied activities
  • 2 commercial products
  • Aldesleukin (IL-2) Proleukin (Chiron)
  • Oprelvekin (IL-11), Neumega (Genetic Institute)

38
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39
Recombinant IL-2
IL-2 - made by activated T cells and induces T
cell proliferation and differentiation. Aldesleuk
in (Proleukin)- recombinant IL-2 produced in E.
coli, not glycosylated single aa change cysteine
125 - serine Approved in 1998 for treatment of
metastatic melanoma. Mechanism of action not
entirely clear - activation of T cells and
natural killer cells thought important.
40
Recombinant IL-11
IL-11 is a thrombopoietic growth factor -
stimulates the proliferation of hematopoietic
stem cells and megakaryocyte proliferation and
maturation - leads to increased platelet
production Recombinant IL-11 - oprelvekin
(Neumega) produced in E. coli non-glycolylated
lacks N-terminal proline residue otherwise same
as native IL-11 no loss of biological
activity Used to reduce need for platelet
transfusions following myelosuppressive
chemotherapy
41
Approved Biological ProductsInterferons
Generic Name Brand Name Company Therapeutic
Area (1st Date of Approval) Interferon
alfa-n1 Wellferon (GlaxoSK) Chronic hepatitis C
(1999) Interferon alfa-2a Roferon-A (Roche) Hai
ry cell leukemia (1986) AIDS-related Kaposi's
sarcoma (1988) CML (1997) Interferon
alfa-2b Intron-A (Schering) Hairy cell leukemia
(1986) AIDS-related Kaposi's
sarcoma (1988) Chronic hepatitis, types B
(1992) and C (1991) Condylomata acuminata
(1988) Malignant melanoma (1995) NHL
(1997) Interferon alfa-n3 Alferon-N (Interferon
Condylomata acuminata (1989) Sciences) Inter
feron gamma-1b Actimmune (InterMune) Chronic
granulomatous disease (1990) Osteoporosis
(2000) Interferon beta-1b Betaseron (Berlex) Acu
te relapsing-remitting multiple sclerosis
(1993) Interferon beta-1a Avonex (Biogen) Acute
relapsing-remitting multiple sclerosis
(1996) Rebif (Serono)
(2002) Interferon alfacon-1 Infergen (InterMu
ne) Hepatitis C (Naive and Relapse )
(1997) Peg-Interferon-2a Pegasys
(Roche) Hepatitis C (2000) Peg-Interferon-2b PEG
-Intron A (Schering) Hepatitis C (2001)
42
Top 20 Biotech Products by Sales
Top 50 Biologicals in 2000 20 B Above 33
Products in 2002 26 B
Source Med Adv News, Vol.20 (5), 2001 most
drugs are 2002 sales noted by an , based on 2003
web sites Sales dollars are in millions
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