Vaxil BioTherapeutics Ltd.

Vaxil BioTherapeutics Ltd.

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Developing the next generation Developing the next generation Of therapeutic vaccinesOf therapeutic vaccines

Vaxil BioTherapeutics Ltd. 2

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.

Vaxil BioTherapeutics: Vaxil BioTherapeutics: OverviewOverview


Technological and therapeutic advantages


Vaccines for Adoptive immunity:Vaccines for Adoptive immunity: Rational & Rational &

ChallengesChallenges

Goal: Obtain Robust and Comprehensive CD4+ plus CD8+ Goal: Obtain Robust and Comprehensive CD4+ plus CD8+ response but maintain antigen specificityresponse but maintain antigen specificity

Antigen selection is the first and most critical parameter Antigen selection is the first and most critical parameter in designing any type of vaccinein designing any type of vaccine


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.

T-cell Vaccines :T-cell Vaccines : Rational & ChallengesRational & Challenges


The research hypothesis in Vaxil’s new paradigm:

“Do specific defined protein domains have different epitope densities?”

T- cells Vaccine: T- cells Vaccine: A new paradigm A new paradigm

Can the advantages in these two approaches be combined?

Kovjazin et al., Mol. Immunol, April 2011


Vaccine design: Vaccine design: A new paradigm A new paradigm

Kovjazin et al., Mol. Immunol, 2011

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.


Vaxil’s technological approachVaxil’s technological approach: : VaxHit (I)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


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.

Vaxil’s technological approachVaxil’s technological approach: : VaxHit (II)VaxHit (II)

Kovjazin et al., Mol. Immunol, April 2011


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Therapeutic vaccines: Therapeutic vaccines: The essentialsThe essentials

Target: the antigen

Delivery: presenting the

antigen

Adjuvant: boosting

the immune response

Vaxil’s vaccines uniquely provide a solution for all 3 requirements using a

single sequence


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Vaxil’s approach: Vaxil’s approach: Comparison vs. current solutionsComparison vs. current solutions

Score: Score: +Poor, ++Moderate, +++Excellent solution


ImMucinA novel therapeutic vaccine with promiscuous MHC binding for the treatment of MUC1-expressing tumors


ImMucin:ImMucin: Potential for “Pipeline In A Product”Potential for “Pipeline In A Product”

Indication

Patient Population

Lung, Prostate, Colorectal, Breast, Ovary, Thyroid, Pancreatic, Lung, Prostate, Colorectal, Breast, Ovary, Thyroid, Pancreatic, RCC, TCC, RCC, TCC,

Multiple MyelomaMultiple Myeloma, Leukemia (AML,ALL CML), Lymphomas, Leukemia (AML,ALL CML), Lymphomas

Solid TumorsSolid Tumors

Non-solid Tumors Non-solid Tumors

Lab

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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.


ImMucin:ImMucin: Potential for “Pipeline In A Product”Potential for “Pipeline In A Product”

* Image from Silvia Von Mensdorff-Pouilly et al , Cancer 3 (3), 3073 2011

Most antibodies

and vaccines

ImMucin vaccine

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.

Cleavage site


ImMucin (VXL100): ImMucin (VXL100): Anti-MUC1 vaccine 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


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ImMucin: ImMucin: in-vitro & ex-vivoin-vitro & ex-vivo CharacterizationCharacterization

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.

Kovjazin et al., Vaccine, May 2011


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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

ImMucin:ImMucin: invivo Characterizationinvivo Characterization


ImMucin: ImMucin: A first in man studyA first in man study

Principle Investigator: Prof. Michael ShapiraDept. of Bone Marrow Transplantation & Cancer Immunotherapy

Hadassah University Hospital, Jerusalem 91120, ISRAEL

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


Thank youThank you

Lior Carmon Founder and CEOVaxil BioTherapeutics Ltd.+ [email protected] www.vaxilbio.com

Vaxil BioTherapeutics Ltd.

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