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

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Elements of an Antibody-Drug Conjugate (ADC) Specific for a tumor-associated antigen that has restricted expression on normal cells.1,2 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 Cytotoxic agent Designed to kill target cells when internalized and released.1,2 References: 1. Carter PJ et al. Cancer J. 2008;14(3):154-169. 2. Senter PD. Curr Opin Chem Biol. 2009;13(3):235-244. 3. Polson AG et al. Cancer Res. 2009;69(6):2358-2364.

Monoclonal Antibodies Have Activity as Single Agents High degree of specificity for tumor antigens1 Generally well-tolerated2 Long half-life resulting in longer systemic exposure2 Act through direct signaling, recruitment of cytotoxic effector cells and complement fixation1,2 Apoptosis through direct intracellular signaling3 Tumor lysis through host immune effector cells3 References: 1. Ducry L et al. Bioconjug Chem. 2010;21(1):5-13. 2. Carter P et al. Am Assoc Cancer Res Educ Book. 2005;2005(1):147-154. 3. Sharkey RM et al. CA Cancer J Clin. 2006;56(4):226-243.

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 Conventional Chemotherapy Antibody-Drug Conjugates Reference: Carter PJ et al. Cancer J. 2008;14(3):154-169. 5 5

Target Antigen Should Be Expressed on Tumor Cells Compared to Healthy Cells Limited or no expression on 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. 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.

Other Potential ADC Antitumor Activities Some ADCs may retain mAb-mediated anticancer activities1,2 Apoptosis through direct intracellular signaling3 Tumor lysis through host immune effector cells3 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 Treat. doi:10.1007/s10549-010-1090-x. 3. Sharkey RM et al. CA Cancer J Clin. 2006;56(4):226-243.

ADCs Link Precision and Potency for Greater Activity In vivo Activity of an ADC and its Components in a Xenograft Mouse Model Untreated Nonbinding ADC Control Antibody Alone (mAb) Admixture (mAb + Cytotoxic Agent Unlinked) ADC (Cytotoxic Agent Linked to mAb) 5/5 Complete Response (CR) This preclinical study demonstrated that the ADC is more active than the antibody alone or the admixture Reference: Doronina SO et al. Nat Biotechnol. 2003;21(7):778-784.

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 * 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.

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. 3. Doronina SO et al. Nat Biotechnol. 2003;21(7):778-784.

References Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: targeted drug delivery for cancer. Curr Opin Chem Biol. 2010;14(4):529-537. 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. 4th ed. New York, NY: McGraw-Hill; 2005:349-375. Carter P, McDonagh CF. Designer antibody-based therapeutics for oncology. Am Assoc Cancer Res Educ Book. 2005;2005(1):147-154. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778-784. Dubowchik GM, Walker MA. Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs. Pharmacol Ther. 1999;83(2):67-123. 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):1458-1465. 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):7063-7070. 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:10.1007/s10549-010-1090-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):2358-2364. Polson AG, Ho WY, Ramakrishnan V. Investigational antibody-drug conjugates for hematological malignancies. Expert Opin Investig Drugs. 2011;20(1):75-85. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. Sharkey RM, Goldenberg DM. Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin. 2006;56(4):226-243. Siu LL, Moore MJ. Pharmacology of anticancer drugs. In: Tannock IF, Hill RP, Bristow RG, Harrington L, eds. The Basic Science of Oncology. 4th ed. New York, NY: McGraw-Hill; 2005:322-348. Trail PA, Bianchi AB. Monoclonal antibody drug conjugates in the treatment of cancer. Curr Opin Immunol. 1999;11(5):584-588.