1. Vaxil BioTherapeutics Ltd.
Developing the next generation
Of therapeutic vaccines

2. Overview 2 2

3. Vaxil BioTherapeutics: Overview
Vaxil has developed VaxHit, a technology to identify Vaccine Candidate (VCs) with the ability to induce specific, robust and broader T-cell immunity for different cancers and key infectious diseases.
Lead product ImMucin, a MUC1 cancer vaccine is being evaluated in a Phase I/II clinical trial in MM patients (HMC, Jerusalem).
Trial regulatory approval covers all MUC1 positive cancers (>90% of cancers).
A second vaccine MTbuVax for Tuberculosis is in preclinical stage of development.
Partnering can be achieved at pre-clinical stage.
VaxHit in-silico technology has been used to identify a pool of potential VCs.
Currently several academic collaborations and one with industry (Immunovaccine: TSX IMV).
Looking for other partners for out-licensing/joint development.
All IP is company owned. 3

4. Technological and therapeutic advantages4 4

5. Vaccines for Adoptive immunity: Rational & Challenges
Antigen selection is the first and most critical parameter in designing any type of vaccine
Goal: Obtain Robust and Comprehensive CD4+ plus CD8+ response but maintain antigen specificity 5

6. T-cell Vaccines : Rational & Challenges
CD8+ and CD4+ T-cells recognize their target antigen (epitope/s) in association with MHC class I and class II molecules.
Hundreds of MHC alleles with different binding properties - every individual has a different set of between 6 and 12 MHC alleles.
For a vaccine to work, it must be able to bind these MHC molecules in different individuals.
There are currently two main approaches for achieving this goal:
Approach 1: use larger sequence/s (entire pathogen/cancer cell/antigen). Statistically contain more epitopes which can bind more combinations of MHC molecules. This reduces the specificity of response >> reduced efficacy and lead to higher side-effects.
Approach 2: identify epitope/s on the target antigen that bind to one more abundant MHC allele e.g. HLA-A2.1. This leads to a specific but weak immune response, applicable only to that proportion of the population with that MHC molecule. 6

7. Can the advantages in these two approaches be combined?
T- cells Vaccine: A new paradigm
Can the advantages in these two approaches be combined?
The research hypothesis in Vaxil’s new paradigm:
“Do specific defined protein domains have different epitope densities?”
Kovjazin et al., Mol. Immunol, April 2011 7

8. Vaccine design: A new paradigm
Signal peptides (SP) and trans-membrane (TM) domains have exceptionally high MHC epitope densities in all human or mouse protein domains. (when TAP wasn't used, P<1.e-8 in human and P<0.05 in mouse genome, t-test between each group and the overall mean of all sampled domains with Bonferroni).
The high epitope density of SP but not TM is corroborated by a high percentage of identified SP epitope in the IEDB (immune epitope) database. Frequency is X3 higher than expected from the distribution of SP in the proteins containing the epitopes (chi square test, p<1.e-6).
The improved MHC binding of these domains relies on their hydrophobic nature but in SP, also on their specific sequence. Only the SP domains had a significantly higher MHC binding compared to their scrambled counterparts (p<0.05), for TAP and Tapasin-independent allele.
Kovjazin et al., Mol. Immunol, 2011

9. Vaxil’s technological approach: VaxHit (I)
Vaxil offers a different approach, combining the advantages of current approaches.
Using VaxHit, we can easily identify the key VCs sequence (entire SP domains) on any given antigen which has the following characteristics:
Small highly defined sequence: VCs that generate a specific immune response with lower side-effects.
Multiple MHC activation: VCs that bind a large proportion of the individual’s MHC repertoire (promiscuous binding). High coverage for both Class I and Class II.
applicable for the majority of the population worldwide.
induces more robust antigen specific CD4+ and CD8+ T-cell activation.
TAP-independent presentation: VCs have a the ability to overcome “immune escape” attempts by tumour cells/intracellular pathogens >>reduces tumor/pathogens resistance.
Kovjazin et al., Mol. Immunol, April 2011 9

10. Vaxil’s technological approach: VaxHit (II)
VaxHit derived VCs vaccines have the following additional properties:
Stand alone products
Delivery: VCs with the ability to efficiently pass through cell membranes in order to be presented to immune cells via MHC binding.
Adjuvant: VCs hydrophobic properties have antigen specific stimulation properties which reduce the dependency for external adjutants.
Kovjazin et al., Mol. Immunol, April 2011 10

11. Therapeutic vaccines: The essentials
Vaxil’s vaccines uniquely provide a solution for all 3 requirements using a single sequence
Adjuvant: boosting the immune response
Delivery: presenting the antigen
Target: the antigen 11 11

12. Vaxil’s approach: Comparison vs. current solutions
Score: +Poor, ++Moderate, +++Excellent solution 12

13. ImMucin
A novel therapeutic vaccine with promiscuous MHC binding for the treatment of MUC1-expressing tumors

14. Label Expansion Potential
ImMucin: Potential for “Pipeline In A Product”
MUC1 is a well characterized TAA with established role as potential target for Immunotherapy.
MUC1 was recently recognized by the National Cancer Institute as one of the three most
important tumor proteins for vaccine development."
Current anti-MUC1 vaccines are directed to an extracellular domain on MUC1, term (TRA)
Tandem Repeat Array, which so far didn’t manifested satisfactory clinical outcome.
MUC1’s wide presence in many cancer types (Expressed >90% of human epithelial tumors)
including cancer stem cells combined with the unique properties of ImMucin allows label
expansion potential.
Indication
Patient Population
Lung, Prostate, Colorectal, Breast, Ovary, Thyroid, Pancreatic, RCC, TCC,
Multiple Myeloma, Leukemia (AML,ALL CML), Lymphomas
Solid Tumors
Label Expansion Potential
Non-solid Tumors

15. Most antibodies and vaccines
ImMucin: Potential for “Pipeline In A Product”
Most development programs are focused on suppressing tumor growth by directing the extracellular portion of MUC1 (TRA domain).
Success to date has been underwhelming using this approach, and tumor growth tends to restart after a short period of suppression. Since the target of these therapies is the extra cellular domain which cleaves and is shed from the cell, it’s not surprising that affected MUC1 proteins — still intact in the cytoplasm — soon regenerate and continue the process of tumor cell growth.
Vaxil approach to target the intracellular SP domain, suggest for the first time a new paradigm for targeting MUC1.
Most antibodies and vaccines
ImMucin vaccine
Cleavage site
* Image from Silvia Von Mensdorff-Pouilly et al , Cancer 3 (3),

16. ImMucin (VXL100): Anti-MUC1 vaccine
A 21mer peptide containing the entire signal peptide (SP) domain of the MUC1 TAA.
Novel mechanism-of-action:
New strategy targeting MUC1’s SP vs. TRA (improved specificity>>potency).
Broader and more robust immune activation of both CD4+ & CD8+ T-cells.
Designed to be applicable to the majority of the target patient population. (Universal).
Dual MOA: TAP-dependent and independent T-cell activation. A real answer for tumor tendency to escape specific immunity.
Internal adjuvant properties (administration with GM-CSF without additional adjutants).
Potential synergy with other modalities e.g. DC, TIL, Agonist antibodies etc. for in-vivo/ex-vivo use.
Kovjazin et al., Vaccine, May 2011 16

17. ImMucin: in-vitro & ex-vivo Characterization
ImMucin has a pan-HLA activation of CD4+ and CD8+ T-cells in comparison to a number of known 9mer epitopes (in naïve and primed patient-derived PBLs)
Repeated stimulation of PBL with ImMucin, increased the % of CD4+ and CD8+ population as well as of CD8+CD45RO+ and CD4+CD45RO+ memory T-cell population.
Anti-ImMucin human T-cell lines recognize the 21mer ImMucin as a set of 9mer epitopes and manifest specific response proliferation and cytokine release against them. (cross presentation).
ImMucin is presented on target cells for MUC1 specific CTL lysis.
ImMucin manifest TAP-independent presentation on TAP-deficient tumor cells.
ImMucin immunogenicity profile (proliferation) is higher and wider vs. MUC1-TRA-L (VXL25), the API of the most advanced anti-MUC1 vaccine BLP25. 17
Kovjazin et al., Vaccine, May 2011

18. ImMucin: invivo Characterization
ImMucin’s epitopes are naturally presented after vaccination of HHD-2 HLA transgenic mice and BALB/c syngeneic mice. Kovjazin et al., Vaccine, May 2011
ImMucin plus GM-CSF is sufficient for the induction of anti-MUC1 CTL in HHD-2 mice. Kovjazin et al., Vaccine, May 2011
ImMucin without any additional adjuvants is sufficient for the induction of anti-MUC1 CTL and proliferation (CD4 and CD8) in BALB/c mice. (Vaxil unpublished data)
ImMucin is more potent than MUC1-TRA-L (VXL25) in the induction of anti-MUC1 CTL and anti-metastatic response in BALB/c mice. Kovjazin et al., Vaccine, May 2011
ImMucin’s epitope (MUC1-SP-S1) is the only immunogenic epitope in HLA-A2.1/MUC1 double transgenic mice. Stepensky et al., Clin Exp Immunol., 2006
ImMucin’s epitope (MUC1-SP-S2) manifested MUC1 specific response in cancer patients Brossart et al., Blood, 2000 18

19. ImMucin: A first in man study
VAXIL-001
A Phase I/II Open Label Study To Asses The Safety And Efficacy Of ImMucin
In Patients with MUC1-positive, Multiple Myeloma (MM)
Results Coming up 2012
Principle Investigator: Prof. Michael Shapira
Dept. of Bone Marrow Transplantation & Cancer Immunotherapy
Hadassah University Hospital, Jerusalem 91120, ISRAEL 19

20. Thank you Lior Carmon Founder and CEO Vaxil BioTherapeutics Ltd. 20 20 20