new drug discovery can help to kill the cancer cells.

1. Focusing on drugs under clinical trials
Shu Yi
Hamide Rezvani
Seyed Mohammad Motevalli
Mohammad Owais
Evan Atoni
Cancer Nanotechnology
Prof. Nie
Spring 2016

2. Drugs and Companies
• MEDI4736 AstraZeneca
• ABRAXANE Celgene
• Pertuzumab Roche
• DOX Plus Olaratumab Eli Lilly and Company

3. http://www.pmlive.com/top_pharma_list/global_revenues?SQ_DESIGN_NAME=2&#.VwcXsEfhs2_
Top 25 pharma companies by global sales

4. A Global Study to Assess the Effects of MEDI4736
Following Concurrent Chemoradiation in Patients With
Stage III Unresectable Non-Small Cell Lung Cancer
(PACIFIC)

5. Brief Introduction
 MEDI4736 is a cancer drug on Phase III trial from AstraZeneca
 For the treatment of non-small cell lung cancer (NSCLC) and other cancers
 Directed against programmed cell death ligand 1 (PD-L1)
 AZ is a British-Swedish multinational pharmaceutical company headquartered in
London, UK.
 7th largest pharma company with operations in over 100 countries.

6. The combination therapy
 To improve treatment outcomes, A variety of approaches for
combining PD-1/PD-L1 pathway inhibitors with other
therapeutic methods have been explored over the past few years
in an effort to offer more feasible therapeutic options.
 Combination therapy = MEDI4736 + Tremelimumab

7. MEDI4736 + Tremelimumab
• MEDI4736, a monoclonal antibody that targets the
programmed cell death-1 ligand (PD-L1) expressed on
tumor cells, and tremelimumab is a monoclonal antibody
that inhibits cytotoxic T-lymphocyte-associated protein 4
(CTLA-4) found on T cells.
• Activation of both PD-L1 and CTLA-4 pathways blocks
the immune system and inhibits the generation of an
immune response.
• Tumor cells take advantage of this physiological process
to avoid immune detection and cell death. Inhibiting
these proteins with MEDI4736 and tremelimumab
restimulates the immune system to detect and destroy
tumor cells.

9. Preventing PD-L1 from
binding to its receptors on T-
Cells (B7.1) may release the
T-Cells from the Inhibitory
effect of PD-L1
PD-L2 interactions should
not be affected by PD-L1
interference
• Studies suggest PD-L2 is a ligand primarily
expressed on normal tissues and immune cells
and thus not affected

11. Adverse Events
Drug-related adverse events reported in Phase I & II are:
• Fatigue (26 %)
• Diarrhea (21 %)
• Colitis (7 %).
• Increased amylase (13 %).

12. Study Findings
Thus far..
Results demonstrate that the combination of MEDI4736 and
tremelimumab has clinical activity in NSCLC(Non-Small Cell
Lung Cancer) patients, including in patients who lack tumor
expression of PD-L1. Out of 31 evaluable patients, 8 patients
achieved a partial response and 11 patients had stable disease,
while 3 out of 10 patients with PD-L1 negative tumors had a
partial response.

13. Safety and Efficacy Study of Abraxane as Maintenance
Treatment After Abraxane Plus Carboplatin in 1st Line
Stage IIIB / IV Squamous Cell Non-small Cell Lung
Cancer (aboundsqm)
13

14. Celgene
• Celgene Corporation is an American biotechnology
company that manufactures drug therapies for cancer
and inflammatory disorders.
• In 1986, Celgene, originally a unit of the Celanese
Corporation, was spun off as an independent company
following the merger of Celanese Corporation with
American Hoechst Corporation.

15. Abroxane
15
• Protein-bound paclitaxel, also known as nanoparticle albumin–
bound paclitaxel or nab-paclitaxel, is an injectable formulation of
paclitaxel used to treat breast cancer, lung cancer and pancreatic
cancer, among others. Paclitaxel destroys cancer cells by
preventing the normal breakdown of microtubules during cell
division. In this formulation, paclitaxel is bonded to albumin as a
delivery vehicle.
• The active agent in ABRAXANE is paclitaxel, a microtubule
inhibitor. The chemical name for paclitaxel is 5β,20-Epoxy-
1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-
benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
•

16. Chemical Structure
Paclitaxel is a white to off-white crystalline powder with the empirical formula
C47H51NO14 and a molecular weight of 853.91. It is highly lipophilic, insoluble in
water, and melts at approximately 216°C to 217°C.
The nomenclature for paclitaxel is structured on a tetracyclic 17-carbon
(heptadecane) skeleton. There are a total of 11 stereocenters. The active
stereoisomer is (−)-paclitaxel.
16

18. Side Effects
18
• Blood and lymphatic system disorders: lymphopenia, febrile neutropenia
• Skin and subcutaneous tissue disorders: nail disorder, pruritus
• Nervous system disorders: peripheral motor neuropathy, paraesthesia
• Gastrointestinal disorders: dyspepsia, abdominal pain, dysphagia
• Investigations: blood alkaline phosphatase increased
• Musculoskeletal and connective tissue disorders: back pain, pain in extremity,
musculoskeletal pain
• Metabolic and nutrition disorders: dehydration
• Infections and infestations: bronchitis, upper respiratory tract infection, urinary
tract infection
• Vascular disorders: hypotension, hypertension
• Eye disorders: vision blurred
• Hepatobiliary disorders: hyperbilirubinaemia

19. A Safety and Efficacy Extension Study of Pertuzumab in Patients With
Solid Tumors Previously Enrolled in a Hoffmann-La Roche-Sponsored
Pertuzumab Clinical Trial

20. Roche
• Roche was founded in 1896. It is a leader in research-focused
healthcare with combined strengths in pharmaceuticals and
diagnostics.
• Genentech, United States, is a wholly owned member of the
Roche Group. Roche has a majority stake in Chugai
Pharmaceutical, Japan.

21. Pertuzumab
• Pertuzumab(trade name Perjeta) is a recombinant humanized monoclonal
antibody that targets the extracellular dimerization domain (Subdomain II) of
the human epidermal growth factor receptor 2 protein (HER2). It consists of
two heavy chains and two lights chains that have 448 and 214 residues
respectively.
• Pertuzumab was developed at Genentech and is now owned by Roche which
acquired Genentech in 2009.

22. Its application in Cancer
• Breast cancer that is HER2 positive (HER2+) and has
metastasized (spread to other parts of the body). It is
used in patients who have not been treated with
anticancer drugs for metastatic disease.
• Breast cancer that is HER2+ and is locally advanced,
inflammatory, or early-stage. It is used in patients who
have a high risk that the cancer will metastasize or recur
(come back). It is given as neoadjuvant therapy (to
shrink the tumor before surgery).

23. Mechanism
• Pertuzumab targets the extracellular dimerization domain
(Subdomain II) of the human epidermal growth factor
receptor 2 protein (HER2) and, thereby, blocks ligand-
dependent heterodimerization of HER2 with other HER
family members, including EGFR, HER3, and HER4. As a
result, pertuzumab inhibits ligand-initiated intracellular
signaling through two major signal pathways, mitogen-
activated protein (MAP) kinase, and phosphoinositide 3-
kinase (PI3K). Inhibition of these signaling pathways can
result in cell growth arrest and apoptosis, respectively. In
addition, pertuzumab mediates antibody-dependent cell-
mediated cytotoxicity(ADCC).

24. Mechanism
Pertuzumab

25. Side effects
• Left Ventricular Dysfunction
• Embryo-Fetal Toxicity
• Hypersensitivity Reactions/Anaphylaxis

26. A Study of Doxorubicin Plus Olaratumab
(LY3012207) in Participants With
Advanced or Metastatic Soft Tissue
Sarcoma (ANNOUNCE)

27. Eli Lilly and Company
• American global pharmaceutical company
• located in Indianapolis, Indiana, in the United States.
• The company was founded in 1876 by Col. Eli Lilly, a pharmaceutical chemist.
• ImClone Systems Incorporated is a formerly independent biopharmaceutical
company dedicated to developing biologic medicines in the area of oncology.
• It was founded in 1984 and has its corporate headquarters in Bridgewater, New
Jersey and its research headquarters in New York City.
• On October 6, 2008, it accepted a $6.5 billion acquisition offer from Eli Lilly
and Company, and became a fully owned subsidiary of Eli Lilly and Company
on November 24, 2008.
• In 2014 the use of the ImClone brand name was retired and the former ImClone
research and manufacturing sites were renamed Eli Lilly and Company.

28. Olaratumab
• Olaratumab (IMC-3G3; LY3012207) is a fully human
IgG1 monoclonal antibody.
• It can selectively binds human PDGFRα with high
affinity (Kd 40 pM), blocks PDGF-AA, PDGF-BB, and
PDGF-CC (data not shown) binding, and induces
receptor internalization.
• It inhibits the proliferation and growth of a variety of
human tumor cell lines in vitro and in vivo.

29. Doxorubicine
• An anthracycline antibiotic with
antineoplastic activity
• Doxorubicin intercalates between
base pairs in the DNA helix, thereby
preventing DNA replication and
ultimately inhibiting protein
synthesis.
• It inhibits topoisomerase II which
results in an increased and stabilized
cleavable enzyme-DNA linked
complex during DNA replication and
subsequently prevents the ligation of
the nucleotide strand after double-
strand breakage.
• Doxorubicin also forms oxygen free
radicals resulting in cytotoxicity
secondary to lipid peroxidation of
cell membrane lipids; the formation
of oxygen free radicals also
contributes to the toxicity of the
anthracycline antibiotics, namely the
cardiac and cutaneous vascular
effects.

30. Platelet-derived growth factor receptor alpha
• Embryonic development, cell proliferation, survival and
chemotaxis.
• Promotes or inhibits cell proliferation and cell migration
• Plays an important role in the differentiation of bone
marrow-derived mesenchymal stem cells
• Catalytic activityi
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-
tyrosine phosphate
• Plays a role in cell migration and chemotaxis in wound
healing
The response depends on the
nature of the bound ligand and
is modulated by the formation
of heterodimers between
PDGFRA and PDGFRB

37. Targeting the α Receptor for Platelet-Derived Growth Factor
as a Primary or Combination Therapy in a Preclinical Model
of Prostate Cancer Skeletal Metastasis (Zoledronic acid and
Olaratumab)

40. Side effects
• Hair thinning
• Loss of fertility
• Pain in the mouth, tummy (abdomen), bone, joints, or
area of the tumur
• Loss of appetite
• A rash, or red, dry itchy skin

41. Conclusion