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Nonclinical safety evaluation of immunoconjuates Melissa M Schutten, D Antibody-Drug Conjugates: Modes of Toxicity Melissa M. Schutten, DVM, PhD, DACVP.

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Presentation on theme: "Nonclinical safety evaluation of immunoconjuates Melissa M Schutten, D Antibody-Drug Conjugates: Modes of Toxicity Melissa M. Schutten, DVM, PhD, DACVP."— Presentation transcript:

1 Nonclinical safety evaluation of immunoconjuates Melissa M Schutten, D Antibody-Drug Conjugates: Modes of Toxicity 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 2

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

4 Improving the Therapeutic Window DRUG DOSE TOXIC DOSE (MTD) EFFICACIOUS DOSE (MED) Therapeutic Window TOXIC DOSE (MTD) EFFICACIOUS DOSE (MED) ChemotherapyADC MTD: Maximum tolerated dose; MED: Minimum Efficacious Dose •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 4

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

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

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

8 Genentech Confidential—Internal Use Only Modes of Anti-tumor Activity of ADCs Tumor cytotoxicity is target-directed ADC-Ag binding → internalization in lysosomes → ADC degradation → release of toxin intracellularly → tumor cell death Tumor Cell Tumor Cells 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 8

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 9

10 Genentech Confidential—Internal Use Only 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) Systemic release of toxin •Instability of linker •Catabolism of ADC + Modes of Toxicity of ADCs Normal Cell 10

11 Genentech Confidential—Internal Use Only 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) Systemic release of toxin •Instability of linker •Catabolism of ADC + Modes of Toxicity of ADCs Normal Cell 11

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

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

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

15 Genentech Confidential—Internal Use Only 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) Systemic release of toxin •Instability of linker •Catabolism of ADC •DAR + Modes of Toxicity of ADCs Normal Cell 15

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

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

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

19 MMAE TDC is Better Tolerated Than ADC in Monkeys Junutula, et al., Nat. Biotech., 26(8), 2008 •No neutrophil decreases with TDC compared to equivalent ug/m 2 dose of ADC 19 Repeat IV doses of ADC or TDC, Days 1 and 23:

20 Genentech Confidential—Internal Use Only 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) Systemic release of toxin •Instability of linker •Catabolism of ADC •DAR •Site of conjugation + Modes of Toxicity of ADCs Normal Cell 20

21 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) Systemic release of toxin •Instability of linker •Catabolism of ADC + Modes of Toxicity of ADCs Normal Cell 21

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

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 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 ) Systemic release of toxin •Instability of linker •Catabolism of ADC + Modes of Toxicity of ADCs Normal Cell 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. 25

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 26


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