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Antibody Drug Conjugates
for Cancer
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
of cancer.
♠ ...
ADC timeline
1958
MTX linked
to an
antibody
directed
toward
leukemia
cells
1972
Noncovalent
linked ADC
tested in
animal
mo...
Schematic illustration
of ADC
Mechanism of Action
Binding
ADC binds to
the target
antigen on the
surface of the
tumor cell to
produce an
ADC-antigen
com...
Mechanism of Action
Antibody
• Antibodies are
immunoglobulins made up
of:
2 Light Chains (identical)
~25 KDa
2 Heavy Chains (identical)
~50 KD...
Terminology
MAb: Monoclonal Antibodies
From a biology perspective, the design of an effective ADC
relies on
Selection of an
appropriate
target antigen
Tumor
expr...
Target antigens
 A successful ADC should target a well-internalized antigen
with low normal tissue expression and high ex...
Antigen expression
 In general, optimal ADC targets are homogeneously
and selectively expressed at high density on the su...
Antigen internalization
Ideally, once an ADC binds to a tumor-associated target,
the ADC–antigen complex is internalized i...
Impact of format
 The biological activity of an antibody can depend on
the interaction of its Fc portion with cells that ...
Classification of linkers
Linkers
Cleavable
linkers
Lysosomal
protease
sensitive
linkers
Acid sensitive
linkers
Glutathion...
Cleavable linkers
• This strategy utilizes lysosomal proteases, that recognize and cleave a
dipeptide bond to release the ...
• This strategy exploits the higher concentration of thiols, such
as glutathione, to release the free drug.
• Eg. Disulphi...
Noncleavable linkers
• This approach depends on complete degradation of the
antibody after internalization of the ADC, res...
Cytotoxic drugs
• The drugs being used to construct ADCs generally fall into
two categories:
1) Microtubule inhibitors
2) ...
ADC Design
Antibody Drug Conjugates
Linker
Antibody
Drug
• Targets a well-
characterized
antigen
• Maintains
binding, stab...
Conjugation
Strategies
Chemical
Conjugation
Site-specific
conjugation
Chemical conjugation
• Traditionally, conjugation of linker-drugs to an antibody
takes place at solvent accessible reactiv...
Cysteine conjugation
• Cysteine conjugation occurs after reduction of four inter-
chain disulfide bonds.
• Linker-drugs pe...
Drawbacks of
Chemical conjugation
• ADC species differ in
drug load & conjugation
site.
• Therefore, each species
may have...
Site-specific conjugation
• It has three strategies
1
•Insertion of cysteine residues in the antibody
sequence by mutation...
ADC advantages over
Traditional Chemotherapy
Traditional
Chemotherapy
ADC
Merits of ADC
• Selective delivery to tumor cells
• Specific binding to target antigen
• Large therapeutic index
• Reducti...
Demerits of ADC
• Molecular targets having similar expression may also get exposed
to the drug
• Requires screening of ant...
Characterization of ADC
Drug to Antibody Ratio (DAR)
Drug Distribution
Size Variant Analysis
Charge-Based Separations
Anal...
Approved ADCs
Agent Status Indication Antigen Cytotoxin Linker
Glembatumumab
vedotin
Ph II Advanced
breast
cancer
GPNMB MM...
ADCs are a new class of
drugs designed as
a targeted therapy for the
treatment of cancer.
ADCs are complex
molecules compo...
References
• Heidi L. Perez, Pina M. Cardarelli, Shrikant Deshpande, Sanjeev Gangwar,
Gretchen M. Schroeder, Gregory D. Vi...
• Aditya Wakankar, Yan Chen, Yatin Gokarn and Fredric S. Jacobson, Analytical
Methods For Physicochemical Characterization...
Antibody drug conjugates for cancer
Antibody drug conjugates for cancer
Antibody drug conjugates for cancer
Antibody drug conjugates for cancer
Antibody drug conjugates for cancer
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Antibody drug conjugates for cancer

  1. 1. Antibody Drug Conjugates for Cancer Presented By: Anvita Jadhav M. Pharm (IP)
  2. 2. ♠ Antibody-drug conjugates or 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 linked, via a stable linker with labile bonds, to a cytotoxic (anticancer) drug. What are ADCs ?????????????????
  3. 3. ADC timeline 1958 MTX linked to an antibody directed toward leukemia cells 1972 Noncovalent linked ADC tested in animal models 1975 Covalent linked ADCs tested in animal models 1988 Humanized mAbs reported 2000 First FDA approved ADC (Mylotarg®)
  4. 4. Schematic illustration of ADC
  5. 5. Mechanism of Action Binding ADC binds to the target antigen on the surface of the tumor cell to produce an ADC-antigen complex Internalization Entire antigen-ADC complex is internalized through receptor- mediated endocytosis Degradation ADC is degraded inside the a lysosome to release the cytotoxic drug. Release The cytotoxic drug enters the cytoplasm, where it binds to its molecular target. Cell Death The interaction of the cytotoxic drug with DNA/ microtubules leading to apoptosis. 1 2 3 4 5
  6. 6. Mechanism of Action
  7. 7. Antibody • Antibodies are immunoglobulins made up of: 2 Light Chains (identical) ~25 KDa 2 Heavy Chains (identical) ~50 KDa FabRegion FcRegion Antigen Binding Sites
  8. 8. Terminology MAb: Monoclonal Antibodies
  9. 9. From a biology perspective, the design of an effective ADC relies on Selection of an appropriate target antigen Tumor expression levels Rates of antigen internalization Antibody Fc format
  10. 10. Target antigens  A successful ADC should target a well-internalized antigen with low normal tissue expression and high expression on tumors.  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
  11. 11. Antigen expression  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.
  12. 12. Antigen internalization Ideally, once an ADC binds to a tumor-associated target, the ADC–antigen complex is internalized in a rapid and efficient manner. 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
  13. 13. Impact of format  The biological activity of an antibody can depend on the interaction of its Fc portion with cells that express Fc receptors (FcRs).  Therefore, selection of the appropriate antibody format for an ADC is an important consideration.
  14. 14. Classification of linkers Linkers Cleavable linkers Lysosomal protease sensitive linkers Acid sensitive linkers Glutathione sensitive linkers Noncleavable linkers
  15. 15. Cleavable linkers • 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
  16. 16. • This strategy exploits the higher concentration of thiols, such as glutathione, to release the free drug. • Eg. Disulphide linker Glutathione sensitive linkers
  17. 17. Noncleavable 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.
  18. 18. Cytotoxic drugs • The drugs being used to construct ADCs generally fall into two categories: 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.
  19. 19. ADC Design Antibody Drug Conjugates Linker Antibody Drug • Targets a well- characterized antigen • Maintains binding, stability, internalization, etc. • Minimal nonspecific binding • Cleavable or noncleavable • Stable in circulation • Selective intracellular release of drug • Highly potent • Non-immunogenic • Amenable to modifications for linker attachment
  20. 20. Conjugation Strategies Chemical Conjugation Site-specific conjugation
  21. 21. Chemical conjugation • 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. Lysine conjugation • 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 generated.
  22. 22. Cysteine conjugation • 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.
  23. 23. Drawbacks of Chemical conjugation • ADC species differ in drug load & conjugation site. • Therefore, each species may have differ in in- vivo PK properties. • Batch-to-batch consistency in ADC production is difficult to obtain.
  24. 24. Site-specific conjugation • It has three strategies 1 •Insertion of cysteine residues in the antibody sequence by mutation or insertion 2 •Insertion of an unnatural amino acid 3 •Enzymatic conjugation
  25. 25. ADC advantages over Traditional Chemotherapy Traditional Chemotherapy ADC
  26. 26. 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
  27. 27. 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
  28. 28. Characterization of ADC Drug to Antibody Ratio (DAR) Drug Distribution Size Variant Analysis Charge-Based Separations Analysis of Unconjugated Drug Peptide Mapping Analysis
  29. 29. Approved ADCs Agent Status Indication Antigen Cytotoxin Linker Glembatumumab vedotin Ph II Advanced breast cancer GPNMB MMAE Cleavable, Val-Cit Lorvotuzumab mertansine Ph II MM, solid tumors CD56 DM1 Cleavable, disulfide BT-062 Ph I MM CD138 DM4 Cleavable, disulfide ADCs under Clinical Trials Agent Indication Antigen Cytotoxin Linker Adcetris® (brentuximab vedotin) HL, ALCL CD30 MMAE Cleavable Kadcyla® (trastuzumab emtansine) Her2+ metastatic breast cancer HER2 DM1 Non-cleavable
  30. 30. 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 drug. Site-specific conjugation is preferred over chemical conjugation due to decrease heterogeneity. There are some unresolved issues such as antibody affinity, internalization rate etc Conclusion
  31. 31. References • 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 2008.
  32. 32. • 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 – 510, 2006 • 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

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