P-MUC1C-101: A Stem Cell. for Epithelial-Derived. Memory CAR-T Therapy. Solid Tumors
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1 P-MUC1C-11: A Stem Cell Memory CAR-T Therapy for Epithelial-Derived Solid Tumors Devon J. Shedlock, PhD VP, Preclinical Development September 5 th, 218
2 piggybac Enables Multiple Differentiated CAR-T Product Attributes piggybac is a superior DNA delivery system for developing CAR-T and other gene therapy products Unprecedented cargo capacity (>3X lentivirus) three-inone transgene and possibility of multiple CAR or TCR molecules ITR piggybac TM Transposon CARGO ITR + piggybac TM Transposase Creates highly desirable T Stem Cell Memory (Tscm) Phenotype Non-viral delivery system non-oncogenic and nonmutagenic ITR Cut CARGO ITR High insertion efficiency and stable transgene expression Faster to clinic with lower cost than viral methods GENOMIC DNA ITR Paste CARGO ITR Substantial IP portfolio with no dominant or competing IP 1
3 piggybac Unmatched Cargo Capacity Increases Optionality piggybac effectively delivers multiple full-length CARs in single transposon system # Full-length CARs* Function (Killing) 1 2 BCMA BCMA PSMA 3 4 BCMA PSMA CD19 BCMA PSMA CD19 GD2 * Plus selection gene and marker gene 2
4 Massive piggybac Cargo Capacity Allows for Delivery of Three-In- One Transgene for CAR-T products 1 CAR-T MOLECULE Superior binding molecule Molecule (Centyrin, VH, scfv, etc ) with high-specificity binding Fully human and not susceptible to tonic signaling 2 POSITIVE SELECTION Drug resistance gene permits positive selection ~1% of T-cells in final product express the CAR molecule Predicted to result in better therapeutic index 3 SAFETY SWITCH Incorporates proprietary safety switch Rapid, dose-dependent elimination of engineered T-cells if needed Management of Cytokine Release Syndrome (CRS) or other AEs Insulator Selection Gene Insulator ITR Promoter Safety Switch CAR Molecule Poly(A) ITR TTAA TTAA 3
5 CD45RA Poseida CAR-T Products Comprised of Highly Favorable Stem Cell Memory T Cells Tscm phenotype should increase duration of response and allow for relapse control without re-administration Ability to develop product with high percentage of Tscm cells is a distinct competitive advantage piggybac preferentially transposes in Tscm cells Tscm cells persist and live longer than effector cells Tscm cells can produce potentially unlimited effectors cells Tscm-rich product should lead to better engraftment and better duration of response with the potential for reresponse T EFF T EM T SCM T CM Teff Tem Tscm Tcm Lentivirus-produced products have not achieved high Tscm published percentages ranging from less than 1% to ~14% CD62L 4
6 T scm May Be Key to Potent and Durable Responses Poseida CAR-T Products Comprised of Highly Favorable Stem Cell Memory T Cells Correlates with clinical response Melenhorst J. et al., UPenn (217) 2th ASGCT Basu et al., Adaptimmune (217) CAR-TCR Summit T CM : Larson, Juno (218) AACR Without prior fractionation of T N /T CM, Akt inhibitors and shortened process are mostly successful in increasing T CM during viral manufacture The extreme longevity, the robust proliferative potential and the capacity to reconstitute a wideranging diversity of the T cell compartment make the T scm cell type an ideal cell population to employ in adoptive immunotherapy Gattinoni et al. (29) Nat Med; Hinrichs et al. (29) PNAS; Hinrichs et al (211) Blood; Gattinoni et al. (211) Nat Med; Lugli et al. (213) JCI; Klebanoff et al (216) JCI; Sukumar et al (216) Cell Met; Sabatino et al. (216) Blood; 5
7 CD45RA CD45RA Poseida CAR-T Comprised of Highly Favorable Tscm Teff Tem CD62L Tscm Tcm Naïve/Tscm Tcm Tem Teff P-BCMA-11.5% 85.8%.6% 13.1% CD62L Perforin Adapted from Gattinoni et al. (217) Nat. Med. P-BCMA
8 % T r a n s p o s e d % T ra n s d u c e d piggybac and Lentivirus Modify Different T Cell Subsets piggybac preferentially transposes early Tscm cells, while lentivirus prefers differentiated T cells 6 p i g g y B a c T M 6 L e n tiv iru s C D 4 + T c e lls 4 4 C D 8 + T c e lls 2 2 We purified donor cells to these T-cell subsets and then performed optimized piggybac or optimized lentivirus manufacturing on each subset 7 Cell graphics adapted from Henning et al., Nat. Rev. Immunol., 218
9 T u m o r B u r d e n ( B L I T o t a l F l u x ) Poseida CAR-T scm Unprecedented Preclinical Efficacy P-BCMA-11: Liquid tumor (MM.1S) disseminated IV implantation in NSG mice P-PSMA-11: Solid tumor (LNCaP) SC implantation in NSG mice M u l t i p l e M y e l o m a ( M M. 1 S ) I. V. P r o s t a t e C a n c e r ( L N C a P ) S. C P - B C M A ( 1 2 e 6 ( n = 2 ) ) P - B C M A ( 4 e 6 n = 1 9 ^ ) ( ) T u m r O n y n = 1 ) o l ( L O D T u m o r B u r d e n ( C a l i p e r m m 3 ) 3, 2, 5 2, 1, 5 1, 5 P - P S M A ( 4 e 6 ) C l i n c a S M A c F i l P s v C A R ( 4 e 6 ) P - B C M A 1 4 e 6 ) - 1 ( T c s ( o A R ; 4 e l l N C e 6 ) L O D D a y s P o s t C A R - T A d m i n i s t r a t i o n D a y s p o s t C A R - T A d m i n i s t r a t i o n 8
10 Poseida P-BCMA-11: Phase I Study Ongoing Design Single dose, 3+3 dose escalation + selected expansion Adult subjects with relapsed or refractory MM Key Objectives Safety, maximum tolerated dose and/or optimal dose Anti-myeloma efficacy Expansion and functional persistence of the CARTyrin-T cells 9
11 P-MUC1C-11 Autologous CAR-T Therapy for Multiple Solid Tumors
12 MUC1 Target Has Broad Pan-Tumor Potential Mucin-1 (MUC1) is highly expressed in most epithelial-derived cancers MUC1 normally expressed on apical surface of epithelium Aberrant form of MUC1 is expressed on cancer cells, which is specifically recognized by our binder Target for multiple immunotherapies (e.g. cancer vaccines, antibody therapies) Tumor Type MUC1 Expression Number of Tissues Reference Breast 91% 1,447 Rakha et al (25) NSCLC 99% 231 Merck Serono. Data on file RCCa 84% 133 Langner et al (24) Colorectal 81% 243 Baldus et al (22) Ovarian 83% 63 Chauhan et al (26) H&N SCCa 82% 29 Croce et al (21) Nasopharyngeal 1% 38 Zhong et al (1993) Gastric 77% 136 Utsunomiya et al (1998) Prostate 79% 89 DeNardo et al (25) Pancreatic 81% 53 Qu et al (24) Mesothelioma 75% 2 Saad et al (25) Multiple myeloma 59% 125 Cloosen et al (26) Esophageal 32% 53 Kijima et al (21) Lambrechts et al 11
13 MUC1 is a Highly Complex Protein Single pass Type I transmembrane protein N-terminal subunit (MUC1-N) and C-terminal subunit (MUC1-C) form stable heterodimeric complex Canonical isoform 1 is a 1,255aa protein 42 2aa repeats MUC1 is highly polymorphic; various alleles change number of tandem repeats in N >9 isoforms; many with 2-2 VNTR repeats Sousa et al
14 MUC1 is a Highly Complex Protein MUC1 confined to apical surface of normal epithelial cells Hyperglycosylated on normal cells Polarity is lost in tumor cells Hypoglycosylated on tumor cells; branches seem highly immunogenic Roulois et al Sousa et al 216
15 MUC1 is a Highly Complex Protein MUC1 can be cleaved by proteases MUC1 remains heterodimeric under normal growth conditions ECD is cleaved (ADAM 17/TACE and MMP-MT1) to generate shorter membrane-associated peptide fragments (MUC1-C) MUC1* and MUC1-CTF 15 Cleaved MUC1-N is shed from cell and triggers inflammation Soluble MUC1-N is target for MUC1-N-specific immunotherapies and may limit their efficacy Nath et al
16 MUC1 Comprises Various Epitopes for CAR Targeting Hypoglycosylated branches on tumor cells are highly immunogenic Tn-specific binders recognize cancerassociated Tn glycoforms occurring in VNTR (Posey et al, 216) MUC1-C specific binders Target epitopes in region proximal to cell membrane May be retained post-cleavage Are difficult to produce and currently more rare Tn CARs MUC1-C CARs 15 Adapted from Nath et al 214
17 Many MUC1 Isoforms, But Not All Comprise Tn Epitopes Exon1 Tn Epitopes Exon2 TM MUC1-C Epitopes Exon3 Exon4 Exon3 Exon5 Exon6 16 Exon7 Exon8
18 % C D 1 7 a + Screening CARs Recognizing MUC1 Several CAR candidates exhibited antitumor activity against a MUC1 + cancer cell line We constructed multiple MUC1-C CARs and tested: R a ji (M U C 1 -) mrna CAR Expression in primary human pan T cells R P M I (M U C 1 + ) Confirmed surface expression of all 2 Evaluated antitumor activity against a MUC1+ cancer cell line A few CARs (A,G, and E) expressed MUC1-specific antitumor activity 5 C o n tr o l P C A R T C A R F C A R Y C A R S C A R A C A R G C A R E C A R B C A R K C A R 17
19 C D 1 7 a + % C D 1 7 a + % Screening CARs Recognizing MUC1 G MUC1 CAR exhibited strong antitumor activity against multiple MUC1+ cancer cell lines We assessed mrna CAR activity against MUC1 (full-length Isoform 1): We compared mrna MUC1 (MUC1-C vs TN) CAR activity against several breast cell lines: N o ta rg e t 1 R a ji (M U C 1 -) e R a ji (F L M U C 1 -Is o 1 ) 9 8 N o t a r g e t R a j i ( M U C 1 - ) M D A - M B M C F A C A R G C A R E C A R G C A R T n C A R M o c k 18
20 C D 1 7 a + % MUC1 is Expressed on Numerous Cancers with High Unmet Need Poseida MUC1-C CAR mediates robust anti-tumor activity against multiple tumor lines 9 8 P a n c re a tic B r e a s t M e s o th e lio m a C R & C M L & M M N o rm a l M u rin e 7 & N S C L C C e rv ic a l M C A R -T o n ly B x P C -3 P a n c -1 P L 4 5 S W N o ta rg e t C a p a n -2 M U C 1 -C C A R H s T T -4 7 D M C F -7 (S ig m a ) M D A -M B M C F -7 (A T C C ) B T -2 Z R M S T O H N C I-H N C I-H N C I-H A N C I-H N C I-H S N U -C 1 S W 4 8 L S H e la K R P M I U B 1 A R P -1 M M.1 S A G A G A G R a w A G : F ib r o b la s t - L u n g (M U C 1 l o ) N o rm a l c e ll lin e s A G : F ib r o b la s t - U te ru s e n d o m e tr ia l (M U C 1 - ) A G : E p ith e lia l - B re a s t o rg a n o id (M U C 1 - ) 19
21 % C y t o t o x i c i t y MUC1 is Expressed on Numerous Cancers with High Unmet Need Poseida MUC1-C CAR mediates robust anti-tumor activity against multiple tumor lines including ovarian We assessed P-MUC1C-11 activity against ovarian tumor line (OVCAR3): Strong cytotoxicity h r C y t o t o x i c i t y O V C A R 3 ( O v a r i a n ) M D A. M B ( B r e a s t ) CAR-Ts also proliferated and secreted IFNg 4 M C F 7 ( B r e a s t ) Studies evaluating additional ovarian lines underway 2 2 M o c k ( C o n t r o l ) P - P S M A ( C o n t r o l ) P - M U C 1 C T n - C A R
22 CD45RA CD45RA CD45RA CD45RA CD45RA Poseida piggybac manufacture of P-MUC1C-11 piggybac manufacturing process yields high levels of CAR-T scm Mock P-BCMA-11 P-MUC1C-11 Tn CAR 1 5 Q1 2 Q Q1 1 Q Q1 1 Q Q1 1 Q Q4 Q3 Q4 Q3 Q4 Q3 Q4 Q CD62L CD62L CD62L CD62L Teff Tscm Tem Tcm CD62L 21
23 % K i l l i n g % K i l l i n g Evaluation of P-MUC1C-11 in vitro Robust in vitro Tumor Killing by MUC1-C CAR-T scm 1 B r e a s t c a n c e r M C F B r e a s t c a n c e r M D A - M B P B C M A P - M U C 1 C T n C A R 5 5 M o c k : 2 1 : 5 1 : : 2 1 : 5 1 : 1 1 M u l t i p l e m y e l o m a H N o r m a l c e l l l i n e A G ( M U C 1 - ) : 2 1 : 5 1 : : 2 1 : 5 1 :
24 Evaluation of P-MUC1C-11 in vivo MUC1 CAR-T scm were evaluated in MCF-7 breast cancer orthotopic tumor model Day -21: MCF-7.luc 3.5x1 6 Left FP (n=2) Caliper BLI Imaging Blood Draws Days -21 Efficacy of MUC1 CAR-Tscm (12e6) in breast cancer model MCF-7.luc tumor implanted into left fat pad 21 days prior to CAR-T treatment Also serves as tox model since P-MUC1-11 cross-reacts with murine MUC1-2 7 Day : CAR-T Treatment 1) Tumor only control (n=8) 2) Tumor + P-BCMA-11 control (12e6; n=4) 3) Tumor + P-MUC1C-11 (12e6; n=4) 4) Tumor + Tn CAR (12e6; n=4)
25 2, 5 2, 1, 5 1, , 5 2, 1, 5 1, , 5 2, 1, 5 1, , 5 2, 1, 5 1, Potent in vivo Efficacy of P-MUC1C-11 Tumor elimination in 1% of animals at standard dose in human breast cancer xenograft model c a l i p e r m e a s u r e m e n t s 2, 5 T u m o r V o l u m e ( m m 3 ) 2, 1, 5 1, 5 * * * * * * T u m o r o n l y c o n t r o l ( n = 8 ) P - B C M A 1 1 c o n t r o l ( n = 4 ) T n C A R ( n = 4 ) P - M U C 1 C ( n = 4 ) * a n i m a l s u c c u m e d t o t u m o r D a y s p o s t T c e l l i n j e c t i o n T u m o r V o l u m e ( m m 3 ) * a n i m a l s u c c u m e d t o t u m o r * * * * a n i m a l s u c c u m e d t o t u m o r * * * * a n i m a l s u c c u m e d t o t u m o r D a y s p o s t T c e l l i n j e c t i o n D a y s p o s t T c e l l i n j e c t i o n D a y s p o s t T c e l l i n j e c t i o n D a y s p o s t T c e l l i n j e c t i o n 24
26 Summary: Developing MUC1 CAR-T to Address Multiple Indications Discovery program with compelling preclinical data and multiple development options P-MUC1C-11 demonstrated robust antitumor activity against multiple tumor types P-MUC1C-11 T scm mediated rapid, sustained tumor regression and completely eliminated established tumors in an MCF-7 based orthotopic mouse model Compelling data suggesting molecule is binding tumor-specific MUC1 Preclinical data portends broad product potential 25
27 Acknowledgments Eric Ostertag, M.D., Ph.D, CEO Mark J. Gergen, J.D., CBO & CFO Matthew Spear, M.D., CMO Devon J Shedlock, Ph.D., VP of Preclinical Development Immuno-Oncology Jenessa Smith, Ph.D. Xinxin Wang, Ph.D.* Burton Barnett, Ph.D. Stacey Cranert, Ph.D. Christopher Martin, Ph.D. Elvira Khialeeva, Ph.D. Srinivas Rengarajan, M.S. Yenning Tan, M.S. Rebecca Codde
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