Sumiti Jain. [Poster #2003, Tuesday February 13 th ] February 12 th, 2018

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1 Dual Knock-Out of Endogenous T-Cell Receptor and HLA-Class I using Zinc Finger Nucleases with Site-Specific Insertion of a CD19 CAR: Implications for Allogeneic T Cell Therapy Sumiti Jain February 12 th, 2018 [Poster #2003, Tuesday February 13 th ]

2 Forward Looking Statements This presentation contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, as amended. These forward-looking statements include, but are not limited to, the duration for which existing capital resources can provide for planned operations; the design of clinical trials and expected timing for release of data; the anticipated clinical development milestones and other potential value drivers in the future; the expected benefits of the collaboration with Pfizer; the expected capability of Sangamo s technologies; the ability of Sangamo to research and develop novel gene-based therapies and the anticipated benefits of applying Sangamo s ZFP technology platform to specific human diseases; anticipated benefits from corporate partnerships; and the potential of Sangamo s genome editing technology to treat genetic diseases. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of various factors and uncertainties. Factors that could cause actual results to differ include, but are not limited to, the dependence on the success of clinical trials of lead programs, the lengthy and uncertain regulatory approval process, uncertainties related to the timing of initiation and completion of clinical trials, whether clinical trial results will validate and support the safety and efficacy of Sangamo s therapeutics, the ability to establish strategic partnerships and our ability to control expenses and achieve our milestones that generate revenues under our agreements. Further, there can be no assurance that the necessary regulatory approvals will be obtained or that Sangamo and its partners will be able to develop commercially viable gene-based therapeutics. Actual results may differ from those projected in forward-looking statements due to risks and uncertainties that exist in Sangamo s operations and business environments. These risks and uncertainties are described more fully in Sangamo s Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q as filed with the Securities and Exchange Commission. Forward-looking statements contained in this presentation are based on our current expectations and are made as of the date hereof. Sangamo undertakes no duty to update such information except as required under applicable law. 2

3 Vision: Off-the-shelf allogeneic T-cell therapies cgmp Manufacturing Facility HLA knock-out TCR knock-out Targeted insertion of CAR gene Healthy Donor Apheresis Isolate T-cells from a healthy donor s blood T-cell Manufacturing Transient, non-viral delivery of ZFN mrna to manufacture universal CAR-T cells via singlestep, multiplexed gene editing Harvest & Storage Universal CAR-T cells are harvested, cryo-preserved and stored in a secure cell bank Infusion (Patients) Universal, off-the-shelf CAR-T cells are infused into new patients, on-demand 3

4 Product : Healthy donor allogeneic CAR T cells ZFN-mediated multiplexed gene editing provides precise engineering for superior safety and efficacy 4

5 Toolkit to generate healthy donor allogeneic CAR T cells 1. ZFN: β2m knock-out 2. ZFN: TRAC knock-out 3. AAV6: CD19 CAR targeted insertion (TI) into TRAC 5

6 The ZFN platform for genome editing Precision Ability to target any desired nucleotide Efficiency Ability to edit at the desired target nucleotide Specificity Ability to edit the targeted nucleotide without editing elsewhere in the genome 6

7 ZFN technology innovations: Best-in-class gene editing Innovation Result Efficiency Precision Specificity New linkers for configuring DNA-binding modules 300-fold increase in design options for targeting any given sequence Efficiency Precision Specificity New dimer architectures yield higher modification activity Increase DNA editing efficiency to as high as 99.5% Efficiency Precision Specificity Phosphate contact tuning via replacement of key residues Off-target cleavage undetectable (>1000 fold reduction) 7

8 Single step gene editing of activated T cells 1. Activated T cells 2. ZFN mrna electroporation + 3. AAV6 transduction CD19 CAR into TRAC 4. Gene edited T cells are interrogated by MiSeq (genotype) and FACS (phenotype) 8

9 % TRAC Indel ZFN-KO of TRAC achieves 95-99% loss of surface TCR TRAC-ZFN treated T cells 97% CD3 KO ~1:1 Correlation Genotype and Phenotype 97% CD3neg Untreated control CD3 % CD3-neg 9

10 ZFN-KO of β2m consistently achieves >90% loss of class I HLA β2m-ko Achieves functional loss of HLA Class I expression β2m-zfn treated T cells 91.3% HLA Class I KO 91.3% HLAneg Untreated control HLA Class I 10

11 HLA-ABC Highly efficient double KO and GFP TI into TRAC TRAC + β2m double KO 91.0% double neg GFP TI into TRAC 91.4% GFP expression Unedited T cells Double KO T cells (TRAC/B2M) 91.4% GFPpos CD3 GFP 11

12 % CD19+ K562 AAV TI of CD19 CAR into TRAC yields functional CAR-T cells CAR TI into Double KO ~77.2% CARpos (by Protein L) Specific Lysis of CD19+ K562 cells 4hrs; co-culture of CAR-T cells with K562wt and CD19+ K % CARpos Untreated CD19 CAR TRAC KO CD19 CAR Double KO 0 Protein-L/ CAR E:T Ratio 12

13 Highly efficient genome editing is critical for multiple gene modifications 1 KO + 1 KO + 1 TI Compounded Efficiency Very High High Medium Low 99% x 99% x 99% = 97% 90% x 90% x 90% = 73% 70% x 70% x 70% = 34% 50% x 50% x 50% = 13% 13

14 % EDITING Simultaneous multiplex editing efficiency: 3x ZFN KO + 1x TI Potential Application Universal T cells with checkpoint gene knock-out % 9 6 % 9 3 % 9 1 % 5 0 Single Step Editing ZFN Knock-out 1. TRAC (TCR) 2. β2m (HLA-class I) 3. CISH (checkpoint gene) Targeted Insertion 4. GFP (into TRAC) 0 T C R - 2 M - C I S H - G F P + 76% of cells have all 4 edits 14

15 Acknowledgements Genome Editing Gary Lee Lynn Truong Nimisha Gandhi Anthony Conway and Team Andreas Reik and Team Technology Edward Rebar Jeff Miller and Team Lei Zhang and Team Dave Shivak Yuri Bendana AAV Production Richard Surosky and Team Leadership Sandy Macrae Michael Holmes