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Antibody-Drug Conjugates (ADCs) Empowering monoclonal antibodies to fight cancer.

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Presentation on theme: "Antibody-Drug Conjugates (ADCs) Empowering monoclonal antibodies to fight cancer."— Presentation transcript:

1 Antibody-Drug Conjugates (ADCs) Empowering monoclonal antibodies to fight cancer

2 2 Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA All rights reserved. Produced in USA 10/12 Disclosure / Terms and Conditions SEATTLE GENETICS, INC., IS PROVIDING THIS INFORMATION FOR EDUCATIONAL PURPOSES ONLY, AND NEITHER SEATTLE GENETICS, INC., NOR ITS AGENTS, AFFILIATES, PARTNERS OR LICENSORS ARE PROVIDING THIS INFORMATION TO YOU FOR THE PURPOSES OF GIVING YOU MEDICAL ADVICE THE INFORMATION PRESENTED HEREIN IS COPYRIGHTED TO SEATTLE GENETICS, INC. ANY CHANGES OR MODIFICATIONS TO THE CONTENT OR THE SLIDE DECK MAY NOT BE IMPUTED TO SEATTLE GENETICS, INC., OR ITS AGENTS, AFFILIATES, PARTNERS OR LICENSORS

3 3 Linker Attaches the cytotoxic agent to the antibody. Newer linker systems are designed to be stable in circulation and release the cytotoxic agent inside targeted cells. 1-3 Elements of an Antibody-Drug Conjugate (ADC) References: 1. Carter PJ et al. Cancer J. 2008;14(3): Senter PD. Curr Opin Chem Biol. 2009;13(3): Polson AG et al. Cancer Res. 2009;69(6): Antibody Specific for a tumor- associated antigen that has restricted expression on normal cells. 1,2 Cytotoxic agent Designed to kill target cells when internalized and released. 1,2

4 4 Monoclonal Antibodies Have Activity as Single Agents High degree of specificity for tumor antigens 1 Generally well-tolerated 2 Long half-life resulting in longer systemic exposure 2 References: 1. Ducry L et al. Bioconjug Chem. 2010;21(1): Carter P et al. Am Assoc Cancer Res Educ Book. 2005;2005(1): Sharkey RM et al. CA Cancer J Clin. 2006;56(4): Apoptosis through direct intracellular signaling 3 Tumor lysis through host immune effector cells 3 Act through direct signaling, recruitment of cytotoxic effector cells and complement fixation 1,2

5 5 Rationale for ADCs: to Expand the Therapeutic Window Conventional Chemotherapy Antibody-Drug Conjugates 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 Reference: Carter PJ et al. Cancer J. 2008;14(3):

6 6 Target Antigen Should Be Expressed on Tumor Cells Compared to Healthy Cells Efficient internalization of target antigen increases drug delivery and enhances cell-killing 1,3 Expressed on tumor cells 1,2 Limited or no expression on normal or vital tissues 1,2 References: 1. Alley SC et al. Curr Opin Chem Biol. 2010;14(4): Carter PJ et al. Cancer J. 2008;14(3): Polson AG et al. Expert Opin Investig Drugs. 2011;20(1): Target antigen

7 7 Primary Mechanism of Action of ADCs: Targeted Delivery of a Cytotoxic Agent Reference: Carter PJ et al. Cancer J. 2008;14(3):

8 8 Other Potential ADC Antitumor Activities References: 1. Carter PJ et al. Cancer J. 2008;14(3): Junttila TT et al [published online ahead of print August 21, 2010]. Breast Cancer Res Treat. doi: /s x. 3. Sharkey RM et al. CA Cancer J Clin. 2006;56(4): Some ADCs may retain mAb-mediated anticancer activities 1,2 Apoptosis through direct intracellular signaling 3 Tumor lysis through host immune effector cells 3

9 9 Reference: Doronina SO et al. Nat Biotechnol. 2003;21(7): This preclinical study demonstrated that the ADC is more active than the antibody alone or the admixture In vivo Activity of an ADC and its Components in a Xenograft Mouse Model ADCs Link Precision and Potency for Greater Activity Untreated Nonbinding ADC Control 5/5 Complete Response (CR) Antibody Alone (mAb) Admixture (mAb + Cytotoxic Agent Unlinked) ADC (Cytotoxic Agent Linked to mAb)

10 10 Current ADCs are the culmination of decades of scientific investigation Improved by incorporation of: 1,2 −A more potent cytotoxic agent* −A more stable linker −Optimized ratio of cytotoxic agents per antibody References: 1. Alley SC et al. Curr Opin Chem Biol. 2010;14(4): Hamblett KJ et al. Clin Cancer Res. 2004;10(20): * As demonstrated in preclinical models.

11 11 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 mAbs 1 More potent cytotoxic agents 2 Stable linkers increase target specificity and reduce toxicity 1,3 References: 1. Ducry L et al. Bioconjug Chem. 2010;21(1): Alley SC et al. Curr Opin Chem Biol. 2010;14(4): Doronina SO et al. Nat Biotechnol. 2003;21(7):

12 12 References Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: targeted drug delivery for cancer. Curr Opin Chem Biol. 2010;14(4): Boyer MJ, Tannock IF. Cellular and molecular basis of drug treatment for cancer. In: Tannock IF, Hill RP, Bristow RG, Harrington L, eds. The Basic Science of Oncology. 4 th ed. New York, NY: McGraw-Hill; 2005: Carter P, McDonagh CF. Designer antibody-based therapeutics for oncology. Am Assoc Cancer Res Educ Book. 2005;2005(1): Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3): Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7): Dubowchik GM, Walker MA. Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs. Pharmacol Ther. 1999;83(2): Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21(1):5-13. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102(4): Hamblett KJ, Senter PD, Chace DF, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20): Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer [published online ahead of print August 21, 2010]. Breast Cancer Res Treat. doi: /s x. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker- drug selection. Cancer Res. 2009;69(6): Polson AG, Ho WY, Ramakrishnan V. Investigational antibody-drug conjugates for hematological malignancies. Expert Opin Investig Drugs. 2011;20(1): Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3): Sharkey RM, Goldenberg DM. Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin. 2006;56(4): Siu LL, Moore MJ. Pharmacology of anticancer drugs. In: Tannock IF, Hill RP, Bristow RG, Harrington L, eds. The Basic Science of Oncology. 4 th ed. New York, NY: McGraw-Hill; 2005: Trail PA, Bianchi AB. Monoclonal antibody drug conjugates in the treatment of cancer. Curr Opin Immunol. 1999;11(5):


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