Targeted Immunotherapy Platform Granzyme B Targeted Fusion Proteins - - PowerPoint PPT Presentation
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,
Page 1
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Project presentation | June 2020
Page 2
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Clayton Biotechnologies, Inc. is a for-profit company which facilitates the commercialization
medical discoveries made by the Clayton Foundation for Research and its supporting entities.
► Co Conduct me medical re researc rch for the purpose of discovering the cause, prevention and cure of diseases for the be benefit of
ankind. ► Tr Transfer the the re resulting me medical re researc rch di discov
the general public by patenting and licensing such technology for de developm
into dr drugs gs or
produ
The Clayton Foundation for Research is a nonprofit medical research organization in Houston, Texas established in 1933 by Benjamin Clayton.
Page 3
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Switzerland United States of America
UCSD SALK
UTHSC San Antonio UT-Austin UT-Southwestern MD Anderson UT-Medical Branch Baylor College of Medicine
University of Geneva Me Medi dical research for the pu purpo pose
ring th the cause, pr prevention and d cure of di diseases fo for the benefi fit of f mankind.
Page 4
Clayton Biotechnologies, Inc. www.claytonbiotech.com
growing class of drugs in oncology with antibodies leading the growth
promising anti-cancer therapeutic classes are antibodies inducing tumor cell depletion
antibodies approved or under review are inducing direct tumor cell death; 50% are Antibody-Drug Conjugates (ADC)
exist such as emergence of resistance to ADC, which is a primary factor in relapse
Develop a therapeutic strategy that will maximize anti-tumor efficacy while minimizing any immunosuppressive side effects.
Page 5
Clayton Biotechnologies, Inc. www.claytonbiotech.com
cytotoxic as a delivered payload.
B cells to kill target cells.
target tumors and employed as a Target Cancer Platform.
internalized into a call
relevant product candidates with animal proof of concept.
Page 6
Clayton Biotechnologies, Inc. www.claytonbiotech.com
checkpoints.
and B cell therapy.
released and non-released forms.
Page 7
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Pr Product Ta Target St Status us
Gr GrB/F /Fc/I /IT4
160k 160kDa
Fn14 (Lung, Colon, Breast, Melanoma, Liver) Tox and MTD studies ongoing Stable CHO lines generated Gr GrB/F /Fc/V /VEGF
90k 90kDa
KDR Receptor (Tumor Vasculature) Animal POC pK studies ongoing Gr GrB/F /Fc/4 /4D5
160k 160kDa
Her2/Neu(Breast) Animal POC Gr GrB/F /Fc/a /anti-FR FRa
160k 160kDa
Folate Receptor a (Lung, Colon, Breast) In vitro POC and MOA ongoing Gr GrB/F /Fc/P /PG101
160k 160kDa
EMP2 (Ovarian) In vitro POC Gr GrB/F /Fc/X /XX
160k 160kDa
XX (confidential - Ovarian and other solid tumors) In vivo POC
Page 8
Clayton Biotechnologies, Inc. www.claytonbiotech.com
(Fn Fn14 14) are a TNF superfamily ligand-receptor pair.
Associated wi with tu tumor pr progr gression, in invasio ion an and an angiogenesis Fn14 low levels in normal tissue
highl hly ex expres essed ed in in pa pancreatic, ov
n, non–small cell lung, breast renal, melanoma and esophageal tumors.
Fn14 14 ex expres ession
correlates wi with hi higher her tu tumor gr grade de and/or poor prognosis documented in brain, breast, esophageal, prostate, gastric and bladder cancer.
ü Co Completely Human, novel format containing GrB and IgG CH2 and CH3 domains. ü 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 Cy Cytotoxic against many different tumor cell lines(>100 lines tested)
GrB/Fc/IT4
Page 9
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Tri-Phasic Mechanism of GrB Intracellular Action:
cascade/PARP cleavage
Cytochrome C
Page 10
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Efficacy and Survival Curves of Female Nude Mice with Orthotopically Placed MDA-MB-231/Luc Cells.
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 5 0 0 1 0 0 0 1 5 0 0 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 )
D a y T u m o r v o lu m e (m m 3)
T r e a tm e n t D a y ( i.v .)
Page 11
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Page 12
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Potency and MTD of GrB compared to T-DM1
T-DM1 GrB Constructs MTD in mice 242 mg/m2 Not yet determined- highest dose measured no toxicity: 125 mg/m2 Clinical Doses 300 mg/m2 ~150 mg/m2 Cell Line T-DM1 SYD985 GrB –FC-4D5 SKBR3 (Her2 103%) 115nM 45nM 67nM N87 (Her2 241%) 290nM 170nM 309nM SKOV3 (Her2 176%) 3140nM 230 nM >350nM
Cytotoxicity Profile in Breast Cancer cell lines with different Her2+ levels – similar between ADC and GrB
PROBLEMS WITH ADC
Rapidly hydrolyze in plasma
manufacturing
when released
expression
T-DM1 = Trastuzumab emtansine SYD985 = (vic-)trastuzumab duocarmazine
Page 13
Clayton Biotechnologies, Inc. www.claytonbiotech.com
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
Page 14
Clayton Biotechnologies, Inc. www.claytonbiotech.com
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 ü No normal internalization route ü Enzymatically acts in a signaling cascade ü Cellular resistance unlikely against GrB ü Active in a fusion construct
the “perfect payload”
Page 15
Clayton Biotechnologies, Inc. www.claytonbiotech.com
In Intellectual P Property
Extensive worldwide coverage – patents filed in 2013
Ma Manufacturing
CHO stably transfected clones produced 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
Im Immunogenicity
Human protein already present in serum. Very low potential
Page 16
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Granzyme me B B is a novel payload with a uni unique ue mecha echani nism of f act ction. n.
Human, n , non-im immunogenic ic & use with any targeting molecule that is internalized.
characterized.
low na nano nomolar ra range.
Highly e effective i in v vivo and minimal off- target toxicity in animals.
compared to ADC.
RCB for GrB-Fc FcIT4 T4 (good expression levels)
clinical chemistry.
Seeking partners to rapidly develop a new class of potent, targeted therapeutic agents.
Page 17
Clayton Biotechnologies, Inc. www.claytonbiotech.com
ü Gr Granzyme B naturally found in the body, and the sa safety is is pr promising ü The pa payload ca can be be ge genetically link linked ed to to a ta targeti ting mo moiety without chemical conjugation. ü Targeting moieties can be in the range of 25 25-150 150kD kDa. ü Sc ScFv or
smaller pr protein can be used as a targeting moiety other than antibody, which is important for tissue penetration. ü Fusion constructs can be produced in ma mamma mmalian ce cells (C (CHO ce cells) s). ü Granzyme B plays a role in autoimmunity as it is the ga gateway fo for ch check ckpoint inhib inhibit ition ion.
Page 18
Clayton Biotechnologies, Inc. www.claytonbiotech.com
Clayton Biotechnologies, Inc.
One Riverway, Suite 1520 Houston, TX 77056 Alexandra Richardson, PhD, CLP
+41 763 427 147 | arichardson@claytonbiotech.com www.claytonbiotech.com
Thank you for your attention