Intersection Between ADC Targets and ADC Payloads. Julia Coronella Director of Research Tanabe Research Laboratories October 10, 2016

Transcription

1 Intersection Between ADC Targets and ADC Payloads Julia Coronella Director of Research Tanabe Research Laboratories October 10,

2 ADC Target Selection 101 Overexpression in cancer relative to normal tissues Cell Target Payload Cell surface Internalizes Traffics to lysosomes Public Omics Databases (Examples) for Target Expression Analysis in Cancer Database Source Samples DNA RNA Protein CCLE Novartis, Broad Institute ~1000 cancer cell lines Copy number Affy TCGA cbioportal,mskcc 147 studies of primary human tumors Mutation, copy number, methylation RNASEQ CPTAC NCI, Georgetown Ovarian, breast, colorectral primary human tumors from TCGA Mass spec / Proteomics 2

3 Analysis of Target Expression in Cancer Indications: TCGA RNASEQ Via cbioportal rtal.org/index.do Wang et al., Methods Mol Biol. 2016;1418: Quantitative RNASEQ queries now possible! 3

4 Proteomics as a Source of New Cancer Targets for ADCs Minimal requirement for an ADC target is presence of protein Proteomics can reveal targets not easily identified by transcriptomics (overexpression, splice, posttranslational modification, etc.) Upregulated DDX5 protein but not mrna in lung cancer (Tenzer et al., 2016 Mar 22;7(12): Oncotarget) CPTAC Proteomic data analyses very complex Whiteaker et al., Methods Mol Biol ; 1410:

5 Target Selection 201: Intersection of Target and Payload Expression in indications of interest, payload sensitivity Therapeutic index considerations Tissue-specific toxicity of payload 5

6 Is it Useful to Consider Effectiveness of Payload MOA in Specific Indications Expressing Target? Taxane-sensitive cancers (NSCLC, ovarian, breast) are cumulatively 10/11 for signs of activity with CCD ADCs Taxane-insensitive cancers (gastric, CRC) are 1/7 for signs of activity with CCD ADCs Many caveats to this! Hypothesis-generating only Group 1 Pt + Taxane Indication 2 CCI (non-pt) + Taxane Breast 3 Platinum + CCD (non-ti) Cell cycle independent (CCI) SOC chemo Cell cycle dependent (CCD) SOC chemo Tubulin inhibitor or other CCD ADC with Evidence of Clinical Activity NSCLC Cisplatin Docetaxel 2/2 Ovarian Cisplatin Paclitaxel 4/5 Cyclophosphamide Doxorubicin Paclitaxel 4/4 Gastric Cisplatin Capecitabine 1/4 Colorectal 4 Taxane Pancreatic Oxaliplatin Irinotecan, 5-FU, leucovorin Abraxane, Gemcitabine 5 Targeted only Renal 1/2 6 0/3 0/6

7 Impact of Indication on Toxin Choice: Case Study: SC16LD6.5 in SCLC Anti-DLL3 PBD ADC SCLC not sensitive to tubulin inhibition 9% confirmed ORR to IMMU-132 (SN-38) Indication Cell cycle independent (CCI) SOC chemo Cell cycle dependent (CCD) SOC chemo SCLC Cisplatin Etoposide - Pt-based Presented By Charles Rudin at 2016 ASCO Annual Meeting 7

8 Case Study: TDM1 in Breast vs Gastric Cancers Target Density and/or Warhead Sensitivity? T-DM1 ORR in breast cancer ~43% in EMILIA vs 30% cap + lap T-DM1 ORR in gastric cancer ~20% (GATSBY), no better than taxane HER2 is amplified at approximately equal frequency in breast and gastric cancers, but at higher copy number Frequency of HER gene amplification (cbioportal) G B Amplitude of HER gene amplification (cbioportal) B G 8

9 Impact of Warhead Potency and MOA on Toxin Choice: Therapeutic Index Payload IC50, M (free drug) MOA Cell cycle dependent? Approximate fold selectivity proliferating vs quiescent cells PBD 1E-11 DNA cross-linker No Calicheamicin 1E-10 DNA strand breaks No 1E-02 Duocarmycin 1E-10 DNA alkylator / ALDHi No a-amanitin 1E-10 RNA POLII inhibitor No Auristatin 1E-10 Tubulin inhibitor Yes 2E-04 Maytansine 1E-10 Tubulin inhibitor Yes 1E-05 Irinotecan (SN-38) 1E-09 Topoisomerase inhibitor Yes Cisplatin 1E-08 DNA cross-linker No 2E-00 Gemcitabine 1E-07 Nuceloside analog Yes 1E-03 Cell-cycle independent payloads may be superior for indolent tumors, indolent cellular subsets within tumors, or slower-growing CSC However, may also have more toxicity on slow-growing normal cells Pathway-based resistance?

10 Impact of Warhead MOA on Toxin Choice: Toxicity Case Study LGR5-targeting ACDs Expressed on intestinal cancer and normal stem cells LGR5 ADCs with MMAE vs anthracycline PNU Similar activity in vivo in xenograft study Gut toxicity only with PNU ADC LGR5 stain, normal intestine LGR5 stain, CRC Junttila et al., 18 Nov 2015: Vol. 7, Issue 314, pp. 314ra186 10

11 Common Toxicities of ADC Payloads Payload class Payload MOA Most Frequent Associated Off-Target Toxicities PBD DNA cross-linker Hypocellular marrow (CD33A, Stein, ASH 2015) Thrombocytopenia, serosal effusions, skin reaction (SC16LD6.5, Rudin, 2016) Calicheamicin DNA strand breaks Neutropenia, thrombocytopenia Auristatin MMAE Peripheral neuropathy, GI, neutropenia Tubulin inhibitor MMAF Thrombocytopenia, ocular Maytansine DM-1 Thrombocytopenia, neutropenia Tubulin inhibitor DM-4 Ocular, keratitis, neutropenia Irinotecan SN-38 Topoisomerase inhibitor Neutropenia, GI Thrombocytopenia: FcR-CD32-mediated megakaryocyte tox Neutropenia, other bone marrow, GI, skin: Free toxin / nonspecific pinocytosis uptake of ADC, killing of marrow cells? FcR-mediated? Neuropathy: Inhibition of tubulin function in neuronal cells Ocular? Uppal et al., Clin Cancer Res Jan 1;21(1): Reviews by Heather Donaghy, 2016, Hanson Wade; de Goeji and Lambert, Curr Opin Immunol Volume 40, June 2016, Pages 14 23; Coronella et al.,

12 Therapeutic Index Case Study: Auristatin vs PBD ADCs SC16LD6.5, other PBD ADCs (HER2, CD70): mg/kg Q1-2X typically gives total tumor regression Human SC16LD6.5 MTD ~0.3 mg/kg Q3wks Auristatin ADCs typically give regression at ~10 mg/kg Q2-3X Human auristatin ADCs MTD ~ 1-4 mg/kg CD70 MMAF ADC CD70 PBD ADC DLL3 PBD ADC Q4dx model 0.1 mg/kg 0.3 mg/kg 1 mg/kg Oflazoglu et al., Clin Cancer Res Oct 1;14(19): Jeffrey et al., Bioconjug Chem Jul 17;24(7): Saunders et al., Sci Transl Med Aug 26;7(302):302ra136 12