First-in-Class Humanized Anti-DKK2 for Colorectal Cancer

Strong association of clinical biomarker - elevated DKK2 correlates with poor CRC prognosis. First-in-class therapeutic for colorectal cancer, targeting MSS CRC with multiple novel mechanisms of action and low risk for side effects. Complements current treatments like bevacizumab and shows efficacy in Kras-mutant CRC models. Treatment options for CRC are limited, making Anti-DKK2 a promising addition to improve outcomes for patients. DKK2 expression linked to poor CRC prognosis and increased metastasis.

• Colorectal Cancer
• First-in-Class
• Anti-DKK2
• MSS CRC
• Therapeutic

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1. First-in-Class Humanized Anti- DKK2 for Colorectal Cancer DIANQING DIANQING (DAN) WU, PH.D. WU, PH.D. (DAN) GLADYS PHILLIPS GLADYS PHILLIPS CROFOOT PROFESSOR OF PHARMACOLOGY PROFESSOR OF PHARMACOLOGY CROFOOT VASCULAR BIOLOGY AND VASCULAR BIOLOGY AND THERAPEUTIC PROGRAM THERAPEUTIC PROGRAM YALE CANCER CENTER YALE CANCER CENTER COFOUNDER OF COFOUNDER OF QX INC INC QX THERAPEUTICS, THERAPEUTICS,

2. Strong association of clinical biomarker: elevated DKK2 correlates with poor CRC prognosis Target validated in mouse CRC models Multiple novel mechanisms of action Executive Summary Works with CRC standard of care Broad IP coverage of compositions of matter & uses until 2036-39 Use of Proceeds: IND-enabling studies

3. Treatment options are limited in number and efficacy for the major MSS CRC type Anti-DKK2 addresses many shortcomings of current options A first-in-class therapeutic for colorectal cancer (CRC) Target MSS CRC Multiple novel MOAs Low risk for on-target side effects Complements bevacizumab Efficacy in Kras-mutant CRC model (~40% of advanced CRCs with more limited treatment options) Therapy Type Median Survival Standard chemotherapy FOLFIRI: 5-fluorouracil, folinic acid, and irinotecan ~24 months CRC is the third most common cancer in developed countries 1 million new cases and 500,000 deaths per year One fourth are metastatic CRC (mCRC) with <10% of 5-year survival rate FOLFIRI + Targeted Therapy 26-31 months Bevacizumab ~26 months Cetuximab ~31 months Only for non-Kras mutant subpopulation Immune checkpoint inhibitors No efficacy for the major type of CRCs (Microsatellite Stable or MSS) 5F8= mouse anti-DKK2

4. Validated Target with Three MOAs 1) Immune Enhancing NK/CD8 cell activation Tumoricidal Tumor progression/ Metastasis 2) Anti-Angiogenic Anti- DKK2 Tumor angiogenesis DKK2 3) Anti-Stemness/Anti-metastatic DKK2 knockout reduces intestinal tumor burden in a genetic mouse CRC model LGR5 Cancer initiation/Stemness

5. DKK2 expression correlates with poor outcome for CRC patients and Increased CRC metastasis DKK2 expression is upregulated in human CRCs Rectal Adenocarcinoma 100 p-value 2.37E-17 T-test 10.950 Fold change 2.130 Gene Rank top 8% (1406) p=0.031 Overall survival (%) Clinical Clinical Biomarker Biomarker 80 60 40 20 0 0 50 100 150 Elevated DKK2 in CRC Correlates with Poor prognosis Months Rectum (65) Rectal Adenocarcinoma (65) Low DKK2 expression High DKK2 expression Colorectal Carcinoma p-value 2.74E-7 T-test 7.754 Fold change 15.975 Gene Rank top 11% (2078) Colon (12) Colorectal Carcinoma (70)

6. Humanized Clinical Candidate The humanized anti-DKK2 antibody is not expected to show significant on-target toxicity Humanized anti-DKK2 has the same affinity for DKK2 and activity as mouse anti-DKK2 Human anti-DKK2 is synergistic with Anti-VEGFR, a standard of care drug DKK2 is generally expressed at low levels in normal tissues in human and mice. 150 Binding (%) 100 100 IgG anti-VEGFR Anti-DKK2 Anti-VEGFR+DKK2 Probability of Survival 50 75 Kd=350 pM DKK2 knockout mice show little phenotypes including no hyperplasia 0.002 50 0 0 5 10 15 25 nM 2000 Tumor Volume (mm3) 0 1500 15 16 17 18 19 20 21 Days 22 23 24 25 26 27 28 IgG HXT1-V2 (humanized) 5F8 (mouse) 1000 500 0 6 8 10 Day 12 14

7. Blavatnik Blavatnik Funding for $300K Would Accomplish Two Major Pre Funding for $300K Would Accomplish Two Major Pre- - Clinical Milestones To Accelerate Towards IND Enabling Studies Clinical Milestones To Accelerate Towards IND Enabling Studies Evaluation of the DKK2 biomarker in target CRC patients with recurring or non- response tumors to SOC ($200K) 1 Part 1: Dkk2 assessment method development ($100K) Plasma DKK2 ELISA Anti-DKK2 immunostaining of biopsy materials Quantitative RNAscope of biopsy materials Quantitative proteomic analysis of biopsy materials Part 2: DKK2 assessment of patient samples ($100K) Optimization of clinical candidate humanized anti-DKK2 for affinity, efficacy (anti-drug antibody), and CMC by CRO ($100K) 2 Use of Proceeds Use of Proceeds

8. Next Step through out Next Step through out- -licensing or newco licensing or newco 1 IND-enabling Studies Hybridoma banking GMP scale up of clinical candidate GLP safety and efficacy testing Pre-IND Meeting Complete in ~18 Months Phase 1a/1b Human Study (Stage IV DKK2-positive patients) 2 Primary End Point: o Safety (Dose-limiting toxicities, DLTs) o Pharmacologically active dose (PAD) o Maximum Tolerated Dose (MTD) Secondary End Points o Safety PK parameters o Overall response rate (ORR) o Target engagement Complete in ~24 Months

9. Thank you!

10. Can Anti-DKK2 be used for other cancers? Mechanistically anti-DKK2 should work for tumors with high expression of DKK2. It also works in a PTEN-mutated melanoma model. High DKK2 expression correlates low survival of kidney renal papillary carcinoma and bladder urothelial carcinoma DKK2 is upregulated in Ewing sarcoma, gastric intestinal type adenocarcinoma, pancreatic ductal adenocarcinoma in addition to CRCs and some subtypes of melanoma.

11. Expiration Date Country Status Patent Title/Claims Summary Strong IP Position Broad Coverage of Compositions of Matter and Uses of Two Humanized Preclinical Candidates until 2036-39 China China/HK Issued Pending DICKKOPF2 (DKK2) INHIBITION SUPPRESSES TUMOR FORMATION Compositions of Matter: 5F8 CDRs & DKK@ Immunizing Peptide Methods of Use (Dx, Rx, Combinations) Issued/Validated (BE/CH/DE/ES/FR/IE/SE/UK) & Pending Issued Europe 2035 Japan United States Australia Canada China Europe/HK Israel Japan South Korea United States China/HK Europe Japan United States Issued/Allowed/Pending Pending Pending Issued Pending HUMANIZED ANTI-DKK2 ANTIBODY AND USES THEREOF Compositions of Matter Humanized 5F8 No.1 Methods of Use (Dx, Rx, Combinations) 2036-2038 Pending Issued Pending Issued & Pending Pending Compositions and Methods of Using a Humanized anti- DKK2 antibody Compositions of Matter Humanized 5F8 No.2 Methods of Use (Dx, Rx, Combinations) Pending 2039 Pending Pending