This document discusses the use of monoclonal antibodies in cancer treatment. It begins by introducing monoclonal antibodies and their benefits over conventional chemotherapy, including homogeneity, specificity, fewer side effects, and the ability to be tagged with other compounds. It then describes naked monoclonal antibodies that work alone and conjugated monoclonal antibodies that are joined to chemotherapy drugs or radioactive particles. Several FDA-approved monoclonal antibodies for different cancer types are listed. The mechanisms of action of rituximab, trastuzumab emtansine, and other monoclonal antibodies are described. Current clinical trials and limitations of monoclonal antibody therapy are also summarized.

1. MONOCLONAL ANTIBODY IN
CANCER TREATMENT
Aikyadeep Mandal
M.pharm( Pharmacology), 1st year, 2nd Semester
Roll no. 27720217011

2. INTRODUCTION
Cancer : An abnormal growth of cells
which proliferate in an uncontrolled way and
metastasize
Antibody : An immunoglobulin, a
specialized immune protein, produced
because of the introduction of an antigen into
the body, and which possesses the
remarkable ability to combine with the very
antigen
Monoclonal Antibody : An antibody
produced by a simple clone of cells,
Monoclonal antibody is therefore a single
pure type of antibody

3. Benefits of using monoclonal
antibody
 Homogeneity : Single antibody molecule that binds to the antigen
with the same affinity and promote the same effectors function
 Specificity : Highly specific towards the target antigen
 Less side effects : Much lesser side effects with respect to
conventional chemotherapy
 High efficacy : Efficacy has been found much higher in case of
treating cancer over conventional approach
 Tagging : Can be tagged with chemotherapeutic drugs, radioisotopes
and immunotoxins

4. NAKED& CONJUGATEDMONOCLONALANTIBODIES
 Naked mAbs - Antibodies that work by themselves having no drug or
radioactive material attached to them. These are most common in treating
cancer.
Ex- Alemtuzumab, Trustuzumab, etc.
 Conjugated mAbs- Monoclonal antibodies joined to a chemotherapeutic
agent or to a radioactive particle are called conjugated mAbs
1. Radiolabeled: ibitrumomab tiuxetan,
Tositumomab
2. Chemolabeled: Brentuximab vedotin,
trastuzumab emtansine
3. Immunotoxin: RFB4(dsFv)-PE38

5. TUMOUR ASSOCIATED ANTIGENS
Antigen category
Cluster of
differentiation (CD)
antigen
Glycoproteins
Glycolipids
Vascular targets
Growth factor
Antigens Tumor types expressing antigen
CD20 Non Hodgkin lymphoma
CD30 Hodgkin lymphoma
CD52 Chronic lymphocytic leukemia
EpCAM Epithelial tumors (breast, colon, lung)
gpA33 Colorectal carcinoma
Mucins Epithelial tumors (breast,colon,lung,ovarian)
CA-IX Renal cell carcinoma
PSMA Prostate carcinoma
Gangliosides Neuroectodermal tumors
VEGF Tumor vascularate
VEGFR Epithelium derived solid tumors
ErbB1/EGFR Glioma,lung,breast,colon,head,neck tumors
ErbB2/HER2 Breast,colon,lung,ovarian,prostate tumors
TRAIL R1,R2 Solid tumors & hematological malignancies
RANKL Prostate cancer & metastases

6. Pharmacologic mechanismof action
Adapted from Patrick GM et al., Cancer Biol Med, 2014

7. FDA APPROVED MONOCLONAL ANTIBODIES IN
CANCER TREATMENT
Recently approved drugs are Nivolumab (2015) for NSCL carcinoma, Olaratumab (2016) for
Sarcomas, Avelumab (2017) for metastatic merkel cell carinoma, Atezolizumab (2016) for
Metastatic NSCL carcinoma, Durvalumab (2017) for Metastatic urothelial carcinoma

8. MECHANISMOF ACTIONOF Rituximabon non
b cell Hodgkin’slymphoma
Adapted from Seyfizadeh N, et al., Crit Rev Oncol Hemtol, 2015

9. Random controlled trials done using conventional drug regimen and
Rituximab conjugated with conventional drug
Adapted From the clinical data of research work from Sehn LH., et al and
Fisher RL., et al.
Case study-1

10. MECHANISM OF ACTION OF CONJUGATED MONOCLONAL
ANTIBODY (TRaSTUZUMAB EMTANSINE)
Adapted from LoRusso PM., et al. Clin Cancer Res, 2011

11. (A) (B)
(A) Comparison of in vivo antitumor activity of Trastuzumab and T-DM1 in the
KPL-4 Model
(B) Comparison of dose dependent antitumor activity of Trastuzumab DM1 in
the BT474-EEI model
Adapted from Lewis Philips G D., et al., Targeting HER2 Positive breast cancer with Trastuzumab and
Trastuzumab DM1, an antibody-cytotoxic drug conjugate, Cancer Res.
Case study-2

12. Monoclonal antibodiesCURRENTLYunder clinical
trials

13. Limitations
 In murine xenograft models, mAbs directed against tumour specific
antigens largely remain in the blood and no more than 20% of the
administered dose typically interacts with the tumor
 Although great strides have been made in antibody engineering and
cancer therapy, production cost is estimated at twice that required
for conventional drugs
 Among those mAbs approved for cancer therapy, only two
(trastuzumab, cetuximab) are mainly targeting solid tumours,
whereas over 85% of human cancers are solid tumours, clearly
reflecting the current limitation of mAb treatment
 Although most therapeutic antibodies can trigger complement-
dependent cytotoxicity in vitro, this has not been demonstrated in
vivo so far

14.  More than 90% patients on rituximab therapy experience
infusion related reaction such as cytokine release syndrome and
tumor lysis syndrome
 Intravenous administration of alemtuzumab is associated with
lymphopenia and concomitant immunosuppression
 Conjugated agents such as brentuximab vedotin precipitate
cumulative peripheral neuropathy and myelosuppression is
the main toxicity of 131I-tositumomab and 90Y-ibritumomab
tiuxetan
Limitations

15. References
1. Scott AM, Allison JP, Wolhock JD. Monoclonal antibody in
cancer therapy. Cancer immunity. 2012. 1-5.
2. Coulson A, Levy A, Williams MG. Monoclonal antibodies in
cancer therapy: mechanism, successes, limitations. West Indian
medical journal. 2014. 650-652.
3. Barok M, Joensuu M, Isola J. Trastuzumab emtansine:
mechanism of action and drug resistance. Breast cancer research.
2014. 1-9.
4. Syfizadeh N, Syfizadeh N, Hasenkamp J, Yepeze SH. A molecular
perspective on Rituximab: A monoclonal antibody for B cell non
Hodgkin lymphoma and other affections. Critical reviews in
oncology/hematology. 2015. 1-11 .