Rationale for ADCs:
to Expand the Therapeutic Window
•ADCs are designed to target delivery of a cytotoxic agent
−Increase the delivery of a cytotoxic agent to a tumor
−Limit tissue exposure to free cytotoxic agent
ConventionalAntibody-DrugChemotherapyConjugates
Reference: Carter PJ et al. Cancer J. 2008;14(3):154-169. |
65 |
Target Antigen Should Be Abundantly Expressed on Tumor Cells Compared to Healthy Cells
Target antigen
Expressed abundantly |
Limited or no expression on |
on tumor cells1,2 |
normal or vital tissues1,2 |
• Efficient internalization of target antigen increases drug delivery and enhances cell-killing1,3
References: 1. Alley SC et al. Curr Opin Chem Biol. 2010;14(4):529-537. 2. Carter PJ et al. Cancer J. 2008;14(3):154-169. 3. Polson AG et al. |
66 |
Expert Opin Investig Drugs. 2011;20(1):75-85. |
Primary Mechanism of Action of ADCs: Targeted Delivery of a Cytotoxic Agent
Reference: Carter PJ et al. Cancer J. 2008;14(3):154-169. |
67 |
Other Potential ADC Antitumor Activities
Some ADCs may retain mAb-mediated anticancer activities1,2
Apoptosis through direct |
Tumor lysis through |
intracellular signaling3 |
host immune effector cells3 |
NFКB
References: 1. Carter PJ et al. Cancer J. 2008;14(3):154-169. 2. Junttila TT et al [published online ahead of print August 21, 2010]. Breast Cancer Res |
68 |
Treat. doi:10.1007/s10549-010-1090-x. 3. Sharkey RM et al. CA Cancer J Clin. 2006;56(4):226-243. |
Limitations of Early ADC Technology1-3
•Unstable linker technology: linker breakdown outside target tumor tissue
−Resulting in broader systemic exposure to the cytotoxic agent
−Poor ADC localization to target tumor
•Modest activity
References: 1. Senter PD. Curr Opin Chem Biol. 2009;13(3):235-244. |
2. Chari RVJ. Acc Chem Res. 2008;41(1):98-107. 3. Teicher BA. |
69 |
Curr Cancer Drug Targets. |
2009;9(8):982-1004. |
Next-Generation ADCs:
Engineered & Optimized
Improved by incorporation of:1,2
−A more potent cytotoxic agent*
−A more stable linker
−Improved conjugation technology
−Optimized ratio of cytotoxic agents per antibody
* As demonstrated in preclinical models.
References: 1. Alley SC et al. Curr Opin Chem Biol. 2010;14(4):529-537. 2. Hamblett KJ et al. Clin Cancer Res. 2004;10(20):7063-7070. |
70 |
|
Next-Generation ADCs: Designed to be Stable in Circulation and Release a Cytotoxic Agent in Target Cells
•Newer ADC linker technology is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity1,2,3
References: 1. Ducry L et al. Bioconjug Chem. 2010;21(1):5-13. 2. Alley SC et al. Curr Opin Chem Biol. 2010;14(4):529-537. 3. Teicher BA. |
|
Curr Cancer Drug Targets. 2009;9(8):982-1004. |
71 |
As Demonstrated In Preclinical Models, Next-Generation ADCs Link the Proven Selectivity of
Monoclonal Antibodies With Potent Cytotoxic Agents
Linking individual elements for greater activity
•Selective delivery via mAbs1
•More potent cytotoxic agents2
•Stable linkers increase target specificity and reduce toxicity1,3
References: 1. Ducry L et al. Bioconjug Chem. 2010;21(1):5-13. 2. Alley SC et al. Curr Opin Chem Biol. 2010;14(4):529-537. |
72 |
3. Doronina SO et al. Nat Biotechnol. 2003;21(7):778-784. |
ADC Components
•Targeting AB
–Choice of target (tumor/normal tissue ratio)
–Internalization (must have feature)
–Intracellular trafficking (presumed as important but not clearly spelled)
•Payload
–Highly potent (mostly tubulin active)
•Linker
–Cleavable vs non-cleavable
–Stable in circulation
