O SlideShare utiliza cookies para otimizar a funcionalidade e o desempenho do site, assim como para apresentar publicidade mais relevante aos nossos usuários. Se você continuar a navegar o site, você aceita o uso de cookies. Leia nosso Contrato do Usuário e nossa Política de Privacidade.
O SlideShare utiliza cookies para otimizar a funcionalidade e o desempenho do site, assim como para apresentar publicidade mais relevante aos nossos usuários. Se você continuar a utilizar o site, você aceita o uso de cookies. Leia nossa Política de Privacidade e nosso Contrato do Usuário para obter mais detalhes.
Antibody Drug Conjugates
Presented By: Anvita Jadhav
M. Pharm (IP)
♠ Antibody-drug conjugates or ADCs are a new class of
drugs designed as a targeted therapy for the treatment
♠ ADCs are complex molecules composed of
an antibody linked, via a stable linker with labile bonds,
to a cytotoxic (anticancer) drug.
What are ADCs ?????????????????
Mechanism of Action
ADC binds to
antigen on the
surface of the
tumor cell to
inside the a
where it binds
1 2 3 4 5
From a biology perspective, the design of an effective ADC
Selection of an
A successful ADC should target a well-internalized antigen
with low normal tissue expression and high expression on
Antigen expression on normal tissues can be tolerated if
expression on vital organs is minimal or absent.
Target antigens for ADCs in preclinical & clinical development
Cancer Target Antigens
Breast CD174, GPNMB, CRIPTO & nectin-4 (ASG-22ME)
Ovarian MUC16 (CA125), TIM-1 (CDX-014) & mesothelin
Lung CD56, CD326, CRIPTO, FAP, mesothelin & GD2
Pancreatic CD74, CD227 (MUC-1) & nectin-4 (ASG-22ME)
Prostate PSMA, STEAP-1 & TENB2
In general, optimal ADC targets are homogeneously
and selectively expressed at high density on the surface
of tumor cells.
Homogenous tumor expression (although preferred) is
likely not an absolute requirement.
Ideally, once an ADC binds to a tumor-associated target,
the ADC–antigen complex is internalized in a rapid and
Factors influencing the rate of internalization, such as -
Epitope on the chosen target antigen bound by the ADC
Affinity of the ADC–antigen interaction
Intracellular trafficking pattern of the ADC complex
Impact of format
The biological activity of an antibody can depend on
the interaction of its Fc portion with cells that express Fc
Therefore, selection of the appropriate antibody
format for an ADC is an important consideration.
• This strategy utilizes lysosomal proteases, that recognize and cleave a
dipeptide bond to release the free drug from the conjugate.
• Eg.: Valine - Citrulline linker
• This class of linkers takes advantage of the low pH in the lysosomal
compartment to trigger hydrolysis of an acid labile group within the
linker, & release the drug payload.
• Eg.: Hydrazone linker
Lysosomal protease sensitive linkers
Acid sensitive linkers
• This strategy exploits the higher concentration of thiols, such
as glutathione, to release the free drug.
• Eg. Disulphide linker
Glutathione sensitive linkers
• This approach depends on complete degradation of the
antibody after internalization of the ADC, resulting in release
of the free drug with the linker attached to an amino acid
residue from the mAb.
• Noncleavable linkers has greater stability in circulation
compared with cleavable linkers.
• The drugs being used to construct ADCs generally fall into
1) Microtubule inhibitors
2) DNA-damaging agents
• The percent of an injected antibody that localizes to a solid
tumor is very small (0.003–0.08% injected dose per gram of
tumor); therefore, toxic compounds with sub-nanomolar
potency are desirable.
Antibody Drug Conjugates
• Targets a well-
• Cleavable or noncleavable
• Stable in circulation
• Selective intracellular
release of drug
• Highly potent
• Amenable to
• Traditionally, conjugation of linker-drugs to an antibody
takes place at solvent accessible reactive amino acids such as
lysines or cysteines derived from the reduction of interchain
disulfide bonds in the antibody.
• Results in 0–8 conjugated molecules per antibody
• Conjugation occurs on both the heavy and light chain at ~20
different lysine residues (40 lysines per mAb).
• Greater than one million different ADC species can be
• Cysteine conjugation occurs after reduction of four inter-
chain disulfide bonds.
• Linker-drugs per antibody can range from 0–8, generating
more than one hundred different ADC species.
• ADC species differ in
drug load & conjugation
• Therefore, each species
may have differ in in-
vivo PK properties.
consistency in ADC
production is difficult to
• It has three strategies
•Insertion of cysteine residues in the antibody
sequence by mutation or insertion
•Insertion of an unnatural amino acid
ADC advantages over
Merits of ADC
• Selective delivery to tumor cells
• Specific binding to target antigen
• Large therapeutic index
• Reduction of adverse effects
• Extended and prolonged circulation half life
Demerits of ADC
• Molecular targets having similar expression may also get exposed
to the drug
• Requires screening of antigen of interest
• Premature release of cytotoxic drug
• Sufficient concentration may not be achieved at target site
Characterization of ADC
Drug to Antibody Ratio (DAR)
Size Variant Analysis
Analysis of Unconjugated Drug
Peptide Mapping Analysis
Agent Status Indication Antigen Cytotoxin Linker
Ph II Advanced
GPNMB MMAE Cleavable, Val-Cit
Ph II MM, solid
CD56 DM1 Cleavable, disulfide
BT-062 Ph I MM CD138 DM4 Cleavable, disulfide
ADCs under Clinical Trials
Agent Indication Antigen Cytotoxin Linker
HL, ALCL CD30 MMAE Cleavable
HER2 DM1 Non-cleavable
ADCs are a new class of
drugs designed as
a targeted therapy for the
treatment of cancer.
ADCs are complex
molecules composed of
an antibody, linker and
Site-specific conjugation is
preferred over chemical
conjugation due to
There are some unresolved
issues such as antibody
affinity, internalization rate
• Heidi L. Perez, Pina M. Cardarelli, Shrikant Deshpande, Sanjeev Gangwar,
Gretchen M. Schroeder, Gregory D. Vite And Robert M. Borzilleri, Antibody–Drug
Conjugates: Current Status And Future Directions, Drug Discovery, Pg. No. 1 -
13, December 2013
• Peter D. Senter, Potent Antibody Drug Conjugates For Cancer Therapy, Current
Opinion In Molecular Biology, Pg. No. 1 – 10, 2009
• Pamela A. Trail, Antibody Drug Conjugates As Cancer Therapeutics, Antibodies,
2, Pg. No. 113 - 129, 2013
• Siler Panowski, Sunil Bhakta, Helga Raab, Paul Polakis And Jagath Rjunutula,
Site-Specific Antibody Drug Conjugates For Cancer Therapy, Mabs 6:1, Pg. No. 1
– 12, January/February 2014
• Beverly A. Teicher And Ravi V.J. Chari, Antibody Conjugate Therapeutics:
Challenges And Potential, American Association For Cancer Research, Pg. No.
6389 – 6397, 2011
• Singh Harsharan Pal, Gullaiya Sumeet, Kaur Ishpreet, Antibody Drug Conjugates:
A Leap Ahead In Cancer Treatment, Journal Of Drug Delivery & Therapeutics,
4(3), Pg. No. 52 – 59, 2014
• Blaine Templar Smith, Introduction to Diagnostic and Therapeutic Monoclonal
Antibodies, Volume 17, Lesson 1, Pg. No. 1 – 34, 2012
• Michelle Arkin and Mark M. Moasser, HER2 directed small molecule antagonists,
Current Opinion Investigational Drugs, 9(12) Pg. No. 1264–1276, December
• Aditya Wakankar, Yan Chen, Yatin Gokarn and Fredric S. Jacobson, Analytical
Methods For Physicochemical Characterization Of Antibody Drug Conjugates,
mAbs 3:2, Pg. No. 161 – 172, March/April 2011
• Jun Zhou and Paraskevi Giannakakou, Targeting Microtubules for Cancer
Chemotherapy, Currrent Medicinal Chemistry – Anti-Cancer Agents, Vol. 5, No. 1,
Pg. No. 1 – 7, 2005
• France Carrier, Anne Gatignolo, Mary Christine Hollander, Kuan-Teh Jeang, and
Albert J. Fornace, Induction of RNA-binding proteins in mammalian cells by DNA-
damaging agents, Cell Biology, Vol. 91, Pg. No. 1554-1558, February 1994
• Sarah Payne and David Miles, Chapter 4 Mechanisms of Anticancer Drugs, Part 1
Cell Biology, Pg. No. 34 – 46, 2007
• S. E. Baldus, S. P. Mönig, T. K. Zirbes, J. Thakran3, D. Kothe, M. Koppel, F. G.
Hanisch, J. Thiele, P. M. Schneider, A. H. Hölscher and H. P. Dienes, Lewisy antigen
(CD174) and apoptosis in gastric and colorectal carcinomas: Correlations with
clinical and prognostic parameters, Histology and Histopathology, Pg. No. 503 –
• Patrick J. Burke, Peter D. Senter, David W. Meyer, Jamie B. Miyamoto, Martha
Anderson, Brian E. Toki, Govindarajan Manikumar, Mansukh C. Wani, David J.
Kroll, and Scott C. Jeffrey, Design, Synthesis, and Biological Evaluation of Antibody-
Drug Conjugates Comprised of Potent Camptothecin Analogues, Bioconjugate
Chem., Vol. 20, No. 6, Pg. No. 1242 – 1250, 2009