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Nonclinical safety evaluation of immunoconjuates

Antibody-Drug Conjugates: Modes of Toxicity. Nonclinical safety evaluation of immunoconjuates. Melissa M Schutten , D. Melissa M. Schutten, DVM, PhD, DACVP Safety Assessment Pathology NorCal Society of Toxicology Meeting September 27, 2012. Overview.

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Nonclinical safety evaluation of immunoconjuates

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  1. Antibody-Drug Conjugates: Modes of Toxicity Nonclinical safety evaluation of immunoconjuates Melissa M Schutten, D Melissa M. Schutten, DVM, PhD, DACVP Safety Assessment Pathology NorCal Society of Toxicology Meeting September 27, 2012

  2. Overview • Introduction to Antibody Drug Conjugates (ADCs) • Modes of ADC toxicity • Challenges associated with nonclinical safety evaluation of ADCs • Summary

  3. Anatomy of an Antibody-Drug Conjugate (ADC) Linker stable in circulation Antibody targeted to tumor • Linker biochemistry • Acid labile (hydrazone) • Enzyme dipeptides (cleavable) • Thioether (uncleavable) • Hindered disulfide (uncleavable) • Site of conjugation • Fc, HC, LC • Humanized monoclonal Ab (IgG1) • mAb with Fc modifications (modulate ADCC, CDC activity) • Other mAb fragments Very potent chemotherapeutic drug • Tubulin polymerization inhibitors • Maytansines (DM1, DM4) • Auristatins (MMAE, MMAF) • DNA damaging agents • Calicheamicins • Duocarmycins • Anthracyclines (doxorubicin)

  4. Improving the Therapeutic Window • ADCs can selectively deliver a potent cytotoxic drug to tumor cells via tumor-specific and/or over-expressed antigens • Increase drug delivery to tumor • Reduce normal tissue drug exposure Chemotherapy ADC TOXIC DOSE (MTD) Therapeutic Window TOXIC DOSE (MTD) DRUG DOSE Therapeutic Window EFFICACIOUS DOSE (MED) EFFICACIOUS DOSE (MED) MTD: Maximum tolerated dose; MED: Minimum Efficacious Dose

  5. ADC More Efficacious than Free Cytotoxin in Mice DM1 Free DM1 (cytotoxin) T-DM1 (ADC) Parsons et al, AACR (2007); Modified from S. Spencer

  6. ADC Better Tolerated than Free Cytotoxin in Rats Single IV dose; rats T-DM1 (2040 µg DM1/m²) Body Weight (% change from baseline) Free DM1 (2400 µg DM1/m²) Early mortality (100%) Time (Day) 6 T-DM1: Trastuzumab emtansine

  7. ADC Better Tolerated than Free Cytotoxin in Monkeys 6 mg/kg ADC (~750 μg MMAE/m2) 0.063 mg/kg MMAE (~750 μg MMAE/m2) White Blood Cells • No neutrophil decreases when cytotoxic drug delivered linked to an antibody • ~2-3 times more cytotoxic drug can be given as an ADC A. Kim, D. Danilenko, N. Dybdal, K. Flagella, K. Achilles-Poon

  8. Modes of Anti-tumor Activity of ADCs Tumor Cells Tumor Cell Tumor cytotoxicity is target-enhanced (bystander effect) ADC-Ag binding → extracellular cleavage of toxin → release of toxin in local tumor environment → diffusion of toxin intracellularly to neighboring tumor cells → tumor cell death Tumor cytotoxicity is target-directed ADC-Ag binding →internalization in lysosomes → ADC degradation → release of toxin intracellularly → tumor cell death

  9. Tissue Antigen Characteristics Are Key in ADCs Careful selection of target antigens are an important criterion for both the safety and efficacy of an ADC • The ‘ideal’ tissue antigen should have: • High level of target expression in cancer cells • Little to no expression in normal cells • Expressed on the cell surface • Readily internalized • No shedding into the blood by cleavage of the antigen from cancer cell surface • The number of antigen molecules and antibody binding affinity for the antigen may affect the potency of the ADC

  10. + Modes of Toxicity of ADCs Normal Cell • Systemic release of toxin • Instability of linker • Catabolism of ADC • Unwanted ADC-mediated cytotoxicity • Targeted binding to normal tissues expressing antigen • Off-target (cross reactive) binding to normal tissues • Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis)

  11. + Modes of Toxicity of ADCs Normal Cell • Systemic release of toxin • Instability of linker • Catabolism of ADC • Unwanted ADC-mediated cytotoxicity • Targeted binding to normal tissues expressing antigen • Off-target (cross reactive) binding to normal tissues • Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) 11

  12. Slower Drug Deconjugation With UncleavableLinker Single IV dose 20 mg/kg ADC Concentration (µg/ml)  Total Ab Days post dose  Uncleavable linker  Cleavable linker Polson, et al., Cancer Res., 69(6), 2009

  13. More Stable Linker Reduces Systemic Toxicity of ADC in Rats Single IV dose given on Day 1 :  Change in bodyweight (grams)  Days post dose CD22-DM1 with cleavable linker Polson, et al., Cancer Res., 69(6), 2009

  14. More Stable Linker Reduces Systemic Toxicity of ADC in Rats Single IV dose given on Day 1 : Polson, et al., Cancer Res., 69(6), 2009

  15. + Modes of Toxicity of ADCs Normal Cell • Systemic release of toxin • Instability of linker • Catabolism of ADC • DAR • Unwanted ADC-mediated cytotoxicity • Targeted binding to normal tissues expressing antigen • Off-target (cross reactive) binding to normal tissues • Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis)

  16. Early Observation: Highly Drugged ADCs More Toxic DAR 6 DAR 4 DAR 2 DAR: Drug-to-Antibody Ratio DAR 2 DAR 4 DAR 6

  17. ThioMAb Technology: Controlling Heterogeneity Proportion ADC DAR Proportion TDC DAR Junutula, et al., Nat. Biotech., 26(8), 2008 • Engineered ThioMAb backbone allows more homogenous drug load (MMAE) • Efficacy of TDC  ADC (mg/kg basis) and  2 x ADC (ug MMAE/m2 basis)

  18. Catabolism and Deconjugation of TDC is Slower than ADC in Rats Single dose I.V. PK study: ADC or TDC with matched cytotoxin (MMAE) doses Deconjugation of the Antibody Catabolism of the Antibody Junutula, et al., Nat. Biotech., 26(8), 2008

  19. MMAE TDC is Better Tolerated Than ADC in Monkeys Repeat IV doses of ADC or TDC, Days 1 and 23: • No neutrophil decreases with TDC compared to equivalent ug/m2 dose of ADC Junutula, et al., Nat. Biotech., 26(8), 2008 19

  20. + Modes of Toxicity of ADCs Normal Cell • Systemic release of toxin • Instability of linker • Catabolism of ADC • DAR • Site of conjugation • Unwanted ADC-mediated cytotoxicity • Targeted binding to normal tissues expressing antigen • Off-target (cross reactive) binding to normal tissues • Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis)

  21. + Modes of Toxicity of ADCs Normal Cell • Systemic release of toxin • Instability of linker • Catabolism of ADC • Unwanted ADC-mediated cytotoxicity • Targeted binding to normal tissues expressing antigen • Off-target (cross reactive) binding to normal tissues • Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) 21

  22. Target Antigen Binding Causes “On-Target” Lymphoid Depletion B-cell target depletion in splenic follicles: An example of “exaggerated pharmacology” Anti-cyCD79b Anti-cyCD79b MCC DM1 Vehicle CD20 Ki-67 Polson, et. al, Mol Cancer Ther 8(10), 2009

  23. Target Toxicity to Normal Tissues Results: Seven patients received a total of 23 weekly doses of bivatuzumab mertansine. One patient at the 100 mg/m2 and one at the 120 mg/m2 level experienced stable disease during treatment phase but also developed grade 1 skin toxicity (desquamation). One of them received a second treatment course. At the highest dose level achieved in this study (140 mg/m2), one patient developed toxic epidermal necrolysis after two infusions and died. Massive apoptosis of skin keratinocytes had occurred, whereas only symptomatic therapy for skin toxicity was available. The risk-benefit assessment of all patients treated in the total phase I program (4 clinical trials, 70 patients) turned out to be negative after consideration of this case of a toxic epidermal necrolysis and the skin-related adverse events observed in the other trials. Therefore, development of the conjugate was discontinued.

  24. + Modes of Toxicity of ADCs Normal Cell • Systemic release of toxin • Instability of linker • Catabolism of ADC • Unwanted ADC-mediated cytotoxicity • Targeted binding to normal tissues expressing antigen • Off-target (cross reactive) binding to normal tissues • Non-antigen-mediated ADC uptake (e.g., Fc-mediated uptake, pinocytosis) 24

  25. Summary • An ADC is both a “large molecule” and a “small molecule”. • ADCs hold great promise for improving current oncology therapies. • Highly potent cytotoxic agents are delivered directly to cancer cells, sparing normal tissues. • ADCs tend to be better tolerated than standard chemotherapy. • Increased therapeutic window allows for better balance between safety/efficacy. • There is a fine balance between efficacy and toxicity. • Choice of linker, cytotoxic drug and mAb are all important determinants of safety, PK, and efficacy. • Toxicity is usually antigen-independent, ADC/drug-dependent. • Linker stability, DAR, and site of drug conjugation impacts toxicity.

  26. Acknowledgements Reina Fuji Kelly Flagella Willy Solis Kirsten Achilles-Poon Jacqueline Tarrant Rama Pai Ning Ma Joe Beyer Trung Nguyen Nghi La Fiona Zhong Michelle McDowell Noel Dybdal Donna Dambach Theresa Reynolds Susan Spencer Paul Polakis Bonnee Rubinfeld Jagath Junutula Shang-Fan Yu David Kan Ivan Inigo Wai Lee Wong Kathy Kozak Elaine Mai Jeff Gorrell Michael Mamounas Andrew Polson Seattle Genetics • Angela Hendricks • Amy Oldendorp • Surinder Kaur • Ben Shen • Jay Tibbitts • Joo-Hee Yi • Kedan Lin • Doug Leipold • Ola Saad • Montserrat Carrasco-Triguero • Keyang Xu • Luna Liu • Andy Boswell • Helen Davis • Margaret Kenrick

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