Project presentation | June 2020 Targeted Immunotherapy Platform Granzyme B Targeted Fusion Proteins and Antibodies. Drs. Michael Rosenblum & Stephen Howell Clayton Biotechnologies, Inc. www.claytonbiotech.com Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 1
Clayton Biotechnologies, Inc. is a for-profit company which facilitates the commercialization of medical discoveries made by the Clayton Foundation for Research and its supporting entities. The Clayton Foundation for Research is a nonprofit medical research organization in Houston, Texas established in 1933 by Benjamin Clayton. The two-fold mission of The Foundation is to: ► Co Conduct me medical re researc rch for the purpose of discovering the cause, prevention and cure of diseases for the be benefit of of human ankind. ► Tr Transfer the the re resulting me medical re researc rch di discov overies from the laboratory to the use of the general public by patenting and licensing such technology for de developm opment in into dr drugs gs or or ot other pr produ oducts. Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 2
Medical R l Rese search a at L t Leading ng Re Research Institutions. Switzerland United States of America University of Geneva UCSD UT-Southwestern Me Medi dical research for the pu purpo pose SALK of of discov overi ring th the cause, prevention and pr d cure of di diseases fo for the benefi fit of f mankind. UT-Austin MD Anderson UTHSC UT-Medical Branch San Antonio Baylor College of Medicine Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 3
Ta Targeted Cancer Therapy. • Targeted therapeutics largest growing class of drugs in oncology GOAL with antibodies leading the growth • One of the most successful and promising anti-cancer therapeutic classes are antibodies inducing Develop a therapeutic strategy tumor cell depletion that will maximize anti-tumor • In the last 3 years, 75% of the efficacy while minimizing any antibodies approved or under review immunosuppressive side are inducing direct tumor cell death; effects. 50% are Antibody-Drug Conjugates (ADC) • Despite success of ADCs, problems exist such as emergence of resistance to ADC, which is a primary factor in relapse Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 4
Granzyme B Targeted Gr d Cancer Therapy Pl Platform. • Human pro-apoptotic Granzyme B (GrB) is highly cytotoxic as a delivered payload. • GrB is the cytotoxic protein employed by T cells or B cells to kill target cells. • GrB ( 30kDa ) has been engineered to directly target tumors and employed as a Target Cancer Platform. • Universal use with any targeting molecule that is internalized into a call • Non-toxic in its unconjugated / released form. • GrB Fusion Products active at the low nM range . • Completely human protein - several commercially relevant product candidates with animal proof of concept. Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 5
Mechani nism of sm of Acti tion. on. Circumvents immune • checkpoints. Same MOA as targeted T cell • and B cell therapy. Internalized GrB active in • released and non-released forms. Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 6
Exam Examples es of Gr GrB Co Conjugat gated ed Molec ecules es. Pr Product Ta Target Status St us Tox and MTD studies ongoing Gr GrB/F /Fc/I /IT4 Fn14 (Lung, Colon, Breast, Melanoma, Liver) Stable CHO lines generated 160k 160kDa Animal POC Gr GrB/F /Fc/V /VEGF KDR Receptor (Tumor Vasculature) pK studies ongoing 90k 90kDa Gr GrB/F /Fc/4 /4D5 Her2/Neu(Breast) Animal POC 160k 160kDa Gr GrB/F /Fc/a /anti-FR FRa Folate Receptor a (Lung, Colon, Breast) In vitro POC and MOA ongoing 160k 160kDa GrB/F Gr /Fc/P /PG101 EMP2 (Ovarian) In vitro POC 160kDa 160k XX (confidential - Ovarian and other solid tumors) Gr GrB/F /Fc/X /XX In vivo POC 160kDa 160k Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 7
Gr GrB/F /Fc/I /IT4 – Ta Targeting the Fn14 Receptor. Tumor necrosis factor-like Weak inducer of Apoptosis (TWEAK) and fibroblast growth factor-inducible 14 • ( Fn Fn14 14 ) are a TNF superfamily ligand-receptor pair. angiogenesis Fn14 low levels in normal tissue Associated wi As with tu tumor pr progr gression, in invasio ion an and an • Fn14 is hi highl hly ex expres essed ed in in pa pancreatic, ov ovarian, n, non–small cell lung, breast renal, melanoma and • esophageal tumors. de and/or poor prognosis documented in brain, breast, Fn14 Fn 14 ex expres ession on co correlates wi with hi higher her tu tumor gr grade • esophageal, prostate, gastric and bladder cancer. GrB/Fc/IT4 Co Completely Human, novel format containing ü GrB and IgG CH2 and CH3 domains. Designed for prolonged circulation. ü Targets murine and human Fn14 Fn14 ü 160 160 kD kDa ü Ra Rapi pid d internalization into target cells ü Cytotoxic against many different tumor cell Cy ü lines(>100 lines tested) Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 8
Mole olecula ular Mechani nism sm of of Acti tion on of GrB-Fc of Fc-IT IT4 in in Target Cells. Tri-Phasic Mechanism of GrB Intracellular Action: 1. Activation of the caspase cascade/PARP cleavage 2. Mitochondrial damage- release of Cytochrome C 3. Degradation of Nuclear Matrix Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 9
Preclinical Data - Te Pr Tested vs several di different tu tumor mo models. Efficacy and Survival Curves of Female Nude Mice with Orthotopically Placed MDA-MB-231/Luc Cells . 2 0 0 0 S a lin e G rB -T W E A K (4 0 m g /k g ) G rB -F c -IT 4 (2 0 m g /k g ) G rB -F c -IT 4 (4 0 m g /k g ) T u m o r v o lu m e (m m 3 ) 1 5 0 0 1 0 0 0 5 0 0 0 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 5 7 0 D a y T r e a tm e n t D a y ( i.v .) Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 10
Pr Prolonged serum concentration of of GrB-Fc Fc-IT IT4 in in mic ice. Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 11
Co Compet etitive ve Lan ands dscap ape e – Co Comp mpar ariso son to ADC. C. PROBLEMS WITH ADC Potency and MTD of GrB compared to T-DM1 ADCs are Chemically unstable- • Rapidly hydrolyze in plasma T-DM1 GrB Constructs Expensive, complex, multi-step • Not yet determined- manufacturing MTD in mice 242 mg/m 2 highest dose measured Drug: mAb ratio heterogeneous no toxicity: 125 mg/m 2 • Maytansine and auristatin toxic Clinical Doses 300 mg/m 2 ~150 mg/m 2 • when released Cytotoxicity Profile in Breast Cancer cell lines with different Response impacted by MDR/MRP Her2+ levels – similar between ADC and GrB • expression Cell Line T-DM1 SYD985 GrB –FC-4D5 SKBR3 (Her2 45nM 115nM 67nM 103%) N87 (Her2 241%) 290nM 170nM 309nM SKOV3 (Her2 T-DM1 = Trastuzumab emtansine 3140nM 230 nM >350nM 176%) SYD985 = (vic-)trastuzumab duocarmazine Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 12
Adv Advantages o s of Gr Gran anzym yme B F B Fusi sion co construct cts over ADC. ADC Granzyme B Released form Toxic Non-toxic Conjugation Chemical/enzymatic Recombinant/chemical/enzymatic Linker-IP Yes None MDR resistance Yes None expected due to GrB Manufacturing Complex Simple process Stability Low High COGS High Lower compared to ADC Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 13
Co Compar arison of Protei ein Payl ayloads ads. PE DT dgA drGel GrB Efficacy / Potency +++ +++ +++ +++ +++ Safety (hepatic or renal toxicity) + + + ++ ++ Lack of Immunogenicity - - - - +++ Absence Vascular Leak Syndrome + + + +++ +++ Manufacturing ++ ++ ++ +++ ++ ü Small, non-antigenic human protein Granzyme B ü No normal internalization route ü Enzymatically acts in a signaling cascade the “perfect payload” ü Cellular resistance unlikely against GrB ü Active in a fusion construct Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 14
Ri Risk sk Asse Assessm ssment. In Intellectual P Property Extensive worldwide coverage – patents filed in 2013 CHO stably transfected clones produced Manufacturing Ma Simple 2-step purification process. To Toxicity Released GrB non-toxic. Ongoing toxicity studies suggest very low toxicity Re Resistance ce No cross-resistance to MDR/MRP . No known resistance mechanisms Human protein already present in serum. Im Immunogenicity Very low potential Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 15
Su Summary a and d Ne Next t Ste teps. SUMMARY NEXT STEPS • Gr Granzyme me B B is a novel payload with a Non-human primate studies. • uni unique ue mecha echani nism of f act ction. n. Formulation, stability and • • Hu Human, n , non-im immunogenic ic & use with clinical chemistry. any targeting molecule that is Complete pre-IND package. • GOAL internalized. • Several products generated and Seeking partners to characterized. rapidly develop a new • IC50 in the lo low na nano nomolar ra range. class of potent, targeted • Hi Highly e effective i in v vivo and minimal off- therapeutic agents. target toxicity in animals. • Simple manufacturing and low COGS compared to ADC. • RC RCB for GrB-Fc FcIT4 T4 (good expression levels) Clayton Biotechnologies, Inc. www.claytonbiotech.com Page 16
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