UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): November 4, 2015
PIERIS PHARMACEUTICALS, INC.
(Exact Name of Registrant as Specified in its Charter)
| Nevada | 333-190728 | EIN 30-0784346 | ||
| (State of Incorporation) | (Commission File Number) |
(IRS Employer Identification No.) |
Lise-Meitner-Strasse 30
85354 Freising-Weihenstephan, Germany
(Address of principal executive offices, including zip code)
Registrant’s telephone number, including area code: +49 81 6114 11400
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| ¨ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ¨ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ¨ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ¨ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
| Item 7.01 | Regulation FD Disclosure. |
Attached hereto as Exhibits 99.1 and 99.2 and incorporated by reference herein are industry conference presentations of Pieris Pharmaceuticals, Inc.
The information set forth under this “Item 7.01. Regulation FD Disclosure,” including the exhibit attached hereto, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, nor shall it be deemed incorporated by reference into any filing under the Securities Act of 1933, as amended, except as shall be expressly set forth by specific reference in such filing.
| Item 9.01 | Financial Statements and Exhibits |
(d) Exhibits.
| 99.1 | Industry Conference Presentation of Pieris Pharmaceuticals, Inc. at BIO-Europe 2015, dated November 4, 2015. |
| 99.2 | Industry Conference Presentation of Pieris Pharmaceuticals, Inc. at PEGs Europe Protein & Antibody Engineering Summit, dated November 4, 2015. |
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Dated: November 4, 2015 | PIERIS PHARMACEUTICALS, INC. | |||||
| By: | /s/ Darlene Deptula-Hicks | |||||
| Name: | Darlene Deptula-Hicks | |||||
| Title: | Chief Financial Officer | |||||
EXHIBIT INDEX
| Exhibit No. |
Description | |
| 99.1 | Industry Conference Presentation of Pieris Pharmaceuticals, Inc. at BIO-Europe 2015, dated November 4, 2015. | |
| 99.2 | Industry Conference Presentation of Pieris Pharmaceuticals, Inc. at PEGs Europe Protein & Antibody Engineering Summit, dated November 4, 2015. | |
PRS-300 Series – Multispecific Anticalin® Fusions in Immuno-Oncology BioEurope – Munich November 04, 2015 Exhibit 99.1
Forward Looking Statements Statements in this presentation that are not descriptions of historical facts are forward-looking statements that are based on management’s current expectations and assumptions and are subject to risks and uncertainties. In some cases, you can identify forward-looking statements by terminology including “anticipates,” “believes,” “can,” “continue,” “could,” “estimates,” “expects,” “intends,” “may,” “plans,” “potential,” “predicts,” “projects,” “should,” “will,” “would” or the negative of these terms or other comparable terminology. Factors that could cause actual results to differ materially from those currently anticipated include, without limitation, risks relating to the results of our research and development activities, including uncertainties relating to the discovery of potential drug candidates and the preclinical and clinical testing of our drug candidates; the early stage of our drug candidates presently under development; our ability to obtain and, if obtained, maintain regulatory approval of our current drug candidates and any of our other future drug candidates; our need for substantial additional funds in order to continue our operations and the uncertainty of whether we will be able to obtain the funding we need; our ability to retain or hire key scientific or management personnel; our ability to protect our intellectual property rights that are valuable to our business, including patent and other intellectual property rights; our dependence on third-party manufacturers, suppliers, research organizations, testing laboratories and other potential collaborators; competition in our industry; regulatory developments in the U.S. and foreign countries; as well as those risks more fully discussed in the “Risk Factors” section of our Current Report on Form 8-K filed with the SEC on December 18, 2014, the Company’s annual report on Form 10-K for the fiscal year ended December 31, 2014, the Company’s quarterly reports on Form 10-Q, and the other reports we file with the SEC. In light of these risks, uncertainties and assumptions, the forward-looking statements regarding future events and circumstances discussed in this report may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. The forward-looking statements included in this presentation speak only as of the date hereof, and except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations. PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Company & Anticalin® Technology
Pieris Pharmaceuticals, Inc. Human data demonstrating desired drug-like properties 26 solid tumor patients with VEGF-A antagonist 36 healthy volunteers with hepcidin antagonist Several R&D partnerships generating $40+ M in revenue Potential for future milestone and royalties Retained commercial rights in major markets High Caliber Investors OrbiMed Advisors (~19%), Tekla Capital Management (~10%), Lombard Odier (~6.5%); Ally Bridge Group, Auriga, Emerald Mutual Fund, Forbion, Gilde, GLSV, Novo Nordisk, Sphera Funds, Zydus $110M equity capital raised Proprietary Next-generation Therapeutic Proteins With Several Degrees of Validation Anticalins PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Human Lipocalins – Scaffold for Novel Anticalin® Therapeutics High-affinity (pM) Anticalin bound to Medium target Large target Human lipocalin “template” Small target Human, natural binding proteins Low molecular weight (~1/8 of mAb size) Extracellular Non-immunogenic Very stable “cup-like” structure Highly diverse libraries (>1011) of potential drug candidates Highly automated selection and screening technology (phage display) Deep protein engineering know-how to yield ideal drug candidates PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Pure Anticalin formats Tetracalin mAb-Anticalin formats Fc-Anticalin formats Anticalin Tricalin Duocalin Molecules designed for optimal target engagement and drug like properties Binding site geometry can be adjusted to biological need Going Beyond Anticalin Proteins – Multispecific Drug Candidate Formats PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Anticalin® Product Pipeline PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015 * Until end of Phase 1 Product Target(s) Indication Partner Discovery Preclinical Phase 1 Phase 2 Fully Owned PRS-080 Hepcidin Anemia PRS-060 IL4Ra Asthma PRS-343 CD137/HER2 Immuno-Oncology PRS-300s n.d. Co-Develop-ment PRS-110 cMet Oncology PRS-NN n.d. n.d. PRS-NN n.d. Ophthal-mology PRS-NN n.d. Fully Partnered Daiichi Sankyo n.d. n.d. n.d. n.d. Sanofi n.d. n.d. Stelis Stelis Partner funded Milestones & Royalties Partner funded* Major rights retained n.d. = not disclosed pegylated Anticalin inhalable Anticalin mAb-Anticalin fusion bi-/multispecifics
PRS-300 Series: Multispecifics for Immuno-Oncology
Pieris’ Immuno-Oncology Approach – Localized Immune Activation Mellman et al. Nature 480, 480-489; 2011 Tumor Cell T cell Tumor-targeting mAb Immune system- targeting Anticalin Pieris’ bispecific approach Monospecific Targeting Potential benefits Enhanced tolerability with reduced “off-tumor” effects Tumor-mediated clustering drives signaling by activating receptors Increased efficacy in patients unresponsive to tumor-targeted therapies Challenges Systemic mAbs often show narrow therapeutic window mAbs are poor agonists for certain activating receptors and depend on Fc receptor clustering Pieris is pursuing both activating and inhibitory IO targets PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Costimulatory T cell Engagement in Tumor Microenvironment TNFRS Receptor No activation in periphery T cell receptor MHC-peptide T Cell Targeted Mode of Action Clustering of bispecific molecules in tumor microenvironment to drive costimulatory T cell engagement Maintaining T cell receptor-mediated tumor antigen specificity on activated T cells Costimulatory signal Primary TcR signal Activation Tumor Cell Clustering PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
PRS-300 Series Differentiates from Current IO Approaches Approach Tumor-targeted activation TcR- mediated specificity Toxicity Delivery PRS-300 Yes Yes Expected low Injection Agonistic mAbs No Yes Low to significant Injection BiTE Yes No Observed Slow infusion CAR-T Yes No Observed Individualized adoptive therapy PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Bispecific Geometry May Create Different Pharmacodynamic Effects PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015 13.4 nm Membrane-to-membrane distances play a role in immunoreceptor interactions TNFRS TNFRSL Straightforward access to a range of distances between target binding sites Several formats to interrogate optimal target synapse for tumor cell killing ~15nm ~8nm ~5nm ~5nm Visualization of Antibody-Anticalin fusion ~15nm Expected distances between binding sites in different formats
Pieris IO Pipeline Progressing Multiple Shots on Goal Strategy & Target Idea Discovery / Lead ID Lead Optimization Multispecifics & In vitro PoC Bispecific Program 2014 2015 2016 2017 IO Target Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 CD137 CD137 / HER2 CD137 / n.d. IO Target 2 n.d. / n.d. IO Target 3 n.d. / tbd n.d. / tbd IO Target 4 n.d. / tbd n.d. / tbd IO Target 5 n.d. / tbd n.d. / tbd In vivo PoC IND IND-enabling (GLP / GMP) Today n.d.: not disclosed tbd: 2nd target to be defined PRS-343 PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
PRS-343: First-in-class HER2-CD137 Bispecific
PRS-343: HER2-CD137 Bispecific Multiple Formats Under Preclinical Evaluation CD137 – a TNFR Costimulatory Target Preclinically and clinically validated Marker for tumor-reactive T cells Activation leads to tumor elimination in vivo Signaling included in clinical CAR-T cells mAbs struggle to find therapeutic window Activity depends on Fc receptor interaction Doses required for T cell activation have led to toxicity Current approaches focus on NK activation HER 2 – Validated but not fully exploited Upregulated on several solid tumors with significant unmet medical need Bladder, gastric, ovarian, breast cancer Restricted expression on normal tissue favors immunotherapy approach Bispecific immunotherapy approach may expand responding population HER2+ tumors with lower expression levels not adequately addressed with current therapy PRS-343 CD137-targeting Anticalin HER2-targeting mAb (Trastuzumab derived) PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
CD137-Targeting Anticalin® Has Demonstrated Agonistic Properties Lead CD137-targeting Anticalin identified (several backups available) Affinity: KDhCD137 = 2nM “Non-competitive” CD137 engagement preserves ligand-binding capability to CD137L Leads to T-cell activation in ex vivo human donor cell assay Good biophysical properties: 100% monomeric, high melting temperature (74°C), fully stable at 37°C in PBS or plasma CD137 Anticalin Control Dose dependant activation of T-cells by CD137 cross-linking PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015 IL-2 production Assay (3d in culture)
HER2-CD137 Bispecific Formats Retain Target Binding Capacity PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015 α-HER2 CD137 Ac HER2 CD137 Bispecific formats behave similarly to CD137 and HER2 building blocks Simultaneous target engagement confirmed for bispecific formats
HER2-CD137 Bispecific Formats Exhibit Favorable Biophysical Properties PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015 CD137-HER2-IgG4 (HC, N-term) CD137-HER2-IgG4 (LC, C-term) CD137-HER2-IgG4 (LC, N-term) CD137-HER2-IgG4 (HC, C-term) Constructs stable after one week in PBS at 37°C - no change in SEC profile observed Stability in human plasma also confirmed using a dual binding ELISA Time 0 Time 7day Time 0 Time 7day Time 0 Time 7day Time 0 Time 7day
PoC: T Cell Activation by HER2-CD137 Bispecifics is HER2 Target-Dependent IL-2 response IL-2 response with Her2 blockade Geometry impacts activity of HER2-CD137 Bispecifics Three constructs are capable of activating T cells Activity is HER2 target-dependent Addition of excess Trastuzumab prevents bispecific binding to HER2-positive cells and results in a loss of activity + Trastuzumab Assay design Construct A Construct B Construct C Construct D PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Pharmacokinetics of HER2-CD137 Bispecifics in Mice Comparable to Trastuzumab Trastuzumab Construct A 10mg/kg of bispecifics or Trastuzumab were injected i.v. in male CD-1 mice (3 mice per timepoint) Terminal half-lives of bispecifics range from 15-21 days compared to 13 days for Trastuzumab Beneficial half-life of parental antibody is preserved for all bispecifics or even exceeded PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Preclinical Validation of Tumor-Localized Activation of CD137 (4-1BB) Pastor et al, Molecular Therapy: 2011, 10: 1878-1886 Tumor-targeting CD137 bispecific aptamer leads to tumor growth inhibition and survival advantage in vivo compared to combination therapy Supports Pieris’ bispecifics Mode of Action: Tumor-specific activation of CD137 positive T cells © The American Society of Gene & Cell Therapy PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
PRS-343 – Status & Path Forward PRS-343: HER2-CD137 Bispecifics Exhibit excellent binding and drug-like properties with long half lives in mice Induce strong T cell activation via tumor target-dependent costimulatory T cell engagement Are expected to drive potent local activation of tumor-specific T cells with low systemic toxicity PRS-343: Path to Clinic Cell line development initiated Drug candidate nomination planned for YE 2015 Further ex vivo profiling: Impact of clustering / receptor density on T cell / NK cell activation Killing of target positive tumor cells Testing of different target-positive tumor cells, different T cell subtypes, etc. In vivo evaluation Various animal models including patient derived xenograft (PDX) models Initiate IND enabling studies in 2016 Aim to perform clinical trial in HER2 positive cancer in 2017 PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Summary of Pieris’ Immuno-Oncology Efforts Multispecifics to address non-responding patients and broaden therapeutic window Trafficking immunomodulation to tumor microenvironment Ability to test for optimal synapse through varied geometry Various formats mAb-Anticalin fusions (e.g., PRS-343) Anticalin-Anticalin fusions (undisclosed) Multiple targets Prioritization of costimulatory targets Multiple checkpoint inhibitors also being investigated Each immunomodulatory target combinable with different tumor targets External collaborations complementing internal expertise and resources to advance drug candidates PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
Pieris Pharmaceuticals, Inc. 255 State Street Boston, MA 02109 USA info@pieris.com PRS-300 Series in Immuno-Oncology - BIO EUROPE 2015
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Bispecific Anticalin Fusion Proteins for Localized Targeting of Immune Cells for Application in Immuno-Oncology
Christine Rothe, Ph.D.
PEGS Europe Summit, Nov 4, 2016
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Forward Looking Statements
Statements in this presentation that are not descriptions of historical facts are forward-looking statements that are based on management’s current expectations and assumptions and are subject to risks and uncertainties. In some cases, you can identify forward-looking statements by terminology including “anticipates,” “believes,” “can,” “continue,” “could,” “estimates,” “expects,” “intends,” “may,” “plans,” “potential,” “predicts,” “projects,” “should,” “will,” “would” or the negative of these terms or other comparable terminology. Factors that could cause actual results to differ materially from those currently anticipated include, without limitation, risks relating to the results of our research and development activities, including uncertainties relating to the discovery of potential drug candidates and the preclinical and clinical testing of our drug candidates; the early stage of our drug candidates presently under development; our ability to obtain and, if obtained, maintain regulatory approval of our current drug candidates and any of our other future drug candidates; our need for substantial additional funds in order to continue our operations and the uncertainty of whether we will be able to obtain the funding we need; our ability to retain or hire key scientific or management personnel; our ability to protect our intellectual property rights that are valuable to our business, including patent and other intellectual property rights; our dependence on third-party manufacturers, suppliers, research organizations, testing laboratories and other potential collaborators; competition in our industry; regulatory developments in the U.S. and foreign countries; as well as those risks more fully discussed in the “Risk Factors” section of our Current Report on Form 8-K filed with the SEC on December 18, 2014, the Company’s annual report on Form 10-K for the fiscal year ended December 31, 2014, the Company’s quarterly reports on Form 10-Q, and the other reports we file with the SEC. In light of these risks, uncertainties and assumptions, the forward-looking statements regarding future events and circumstances discussed in this report may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. The forward-looking statements included in this presentation speak only as of the date hereof, and except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations.
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Company and Technology
Overview
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Pieris Pharmaceuticals, Inc.
Anticalins are a novel class of protein therapeutics, proprietary to Pieris, with several degrees of validation
Human data demonstrating desired drug-like properties
– 26 solid tumor patients with VEGF-A antagonist
– 36 healthy volunteers with hepcidin antagonist
Proven track record for successful collaborations with Pharma
Non-Confidential 4
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Human Lipocalins – Scaffold for
Novel Anticalin® Therapeutics
Human lipocalin High-affinity (pM) “template” Anticalin bound to
Small target
Highly diverse phage display libraries (>1011) of potential drug candidates
Human, natural Automated selection and Medium
binding proteins target
screening technology
Low molecular
weight Deep protein engineering
(~1/8 of mAb size)
know-how to yield ideal Extracellular drug candidates
Non-immunogenic
Very stable “cup- Large like” structure target
Non-Confidential
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Going Beyond Anticalin Proteins – Multispecific Drug Candidate Formats
Pure Anticalin formats
Anticalin Duocalin Tricalin Tetracalin
mAb-Anticalin formats
Fc-Anticalin formats
Molecules designed for optimal target engagement and drug-like properties Binding site geometry can be adjusted to biological need
Non-Confidential
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Anticalin® Product Pipeline
Product Target(s) Indication Partner Discovery Preclinical Phase 1 Phase 2
PRS-080 Hepcidin Anemia pegylated Anticalin
Fully PRS-060 IL4Ra Asthma inhalable Anticalin Owned PRS-343 CD137/HER2 IO mAb-Anticalin fusion PRS-300s n.d. IO bi-/multispecifics
PRS-110 cMet Oncology Co- PRS-NN n.d. n.d.
Partner funded* Develop- Major rights retained ment PRS-NN n.d.
Ophthal- Stelis mology
PRS-NN n.d. Stelis
Daiichi n.d. n.d.
Fully Sankyo Partner funded n.d. n.d.
Partnered Milestones & Royalties Sanofi n.d. n.d.
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Until end of Phase 1 n.d. = not disclosed |
Non-Confidential 7
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Anticalin® Product Pipeline
Product Target(s) Indication Partner Discovery Preclinical Phase 1 Phase 2
PRS-080 Hepcidin Anemia pegylated Anticalin
Fully PRS-060 IL4Ra Asthma inhalable Anticalin Owned PRS-343 CD137/HER2 IO mAb-Anticalin fusion PRS-300s n.d. IO bi-/multispecifics
PRS-110 cMet Oncology Co- PRS-NN n.d. n.d.
Partner funded* Develop- Major rights retained ment PRS-NN n.d.
Ophthal- Stelis mology
PRS-NN n.d. Stelis
Daiichi n.d. n.d.
Fully Sankyo Partner funded n.d. n.d.
Partnered Milestones & Royalties Sanofi n.d. n.d.
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PRS-300 Series: Multispecifics for
Immuno-Oncology
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Pieris’ Immuno-Oncology Approach –
Localized Immune Activation
Monospecific Targeting Pieris’ Bispecific Approach
Tumor Tumor- Cell targeting mAb
Immune system- targeting Anticalin
T cell
Mellman et al. Nature 480, 480-489; 2011
Challenges Potential benefits
Systemic mAbs often show narrow Enhanced tolerability with reduced therapeutic window “off-tumor” effects
mAbs are poor agonists for certain activating Tumor-mediated clustering drives signaling receptors and depend on Fc receptor by activating receptors clustering Increased efficacy in patients unresponsive to tumor-targeted therapies
Pieris is pursuing both activating and inhibitory IO targets
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Costimulatory T cell Engagement in Tumor
Microenvironment
T cell costimulation in tumor No T cell costimulation in periphery
Tumor Cell
Tumor target
MHC-peptide
Clustering No clustering
Costimulatory T cell receptor receptor
Costimulatory Primary signal TcR signal
T- Cell No activation Activation
Targeted Mode of Action
Clustering of bispecific molecules in tumor microenvironment drives costimulatory T cell engagement Maintaining T cell receptor-mediated tumor antigen specificity on activated T cells
Non-Confidential
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PRS-343
HER2-CD137 Bispecific Anticalin Fusion Proteins
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PRS-343: HER2-CD137 Bispecifics
Multiple Formats Under Preclinical Evaluation
CD137 – a TNFR Costimulatory Target
Preclinically and clinically validated
Marker for tumor-reactive T cells
Activation leads to tumor elimination in vivo Signaling included in clinical CAR-T cells
mAbs struggle to find therapeutic window
Activity depends on Fc receptor interaction Doses required for T cell activation have led to toxicity
PRS-343
HER 2 – Validated but not fully exploited
Upregulated on several solid tumors with significant unmet medical need
Bladder, gastric, ovarian, breast cancer
Restricted expression on normal tissue favors immunotherapy approach
Bispecific immunotherapy approach may expand responding population
HER2+ tumors with lower expression levels not adequately addressed with current therapy
CD137-targeting Anticalin
HER2-targeting mAb (trastuzumab derived)
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CD137 Targeting Lead Anticalin® Has Demonstrated Agonistic Properties
Binding to CD137
Affinity: KDhCD137 = 2nM
“Non-competitive” CD137 engagement preserves ligand-binding capability to CD137L
Biophysical properties
100% monomeric expression TM = 74°C (DSC)
Fully stable after 1 week at 37°C in PBS, hu or mu plasma
In vitro functional testing
IL-2 Production Assay
CD137 Anticalin
Control
Dose dependent T-cell activation in ex vivo human donor cell assay by CD137 clustering
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CD137-specific Anticalin coated together with subthreshold concentration of aCD3 antibody on ELISA plate |
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HER2-CD137 Bispecific Formats Retain Target Binding Capacity
?-HER2 CD137 Ac
HER2 CD137
Bispecific formats show similar binding to CD137 and HER2 as building blocks
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HER2-CD137 Bispecific Formats Bind Both Targets at the Same Time
Dual binding ELISA data
Dual binding
detection Biotin
assay format
titration
coating
Simultaneous target engagement confirmed for all bispecific formats
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PRS-343 Bispecifics Exhibit
Favorable Biophysical Properties
Storage Stability
Time 0 Time 7day
Freeze / Thaw Stability
Reference Reference Reference Reference
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F/T 3 F/T 3 F/T 3 F/T |
PBS at 37°C
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Plasma and Storage Stability Confirmed
% activity
Plasma stability confirmed
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Fully active after 1 week in human (green) and mouse plasma (blue) at 37°C (0.5mg/ml; dual binding qELISA) |
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wks, 40°C |
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reference |
Storage stability confirmed
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Fully stable and active after 4 weeks at 40°C in PBS (20mg/mL, aSEC and dual |
binding qELISA); *blotted with an off-set on
the y-axis for better visualization
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HER2-CD137 Bispecifics Mode of Action – Relevance of Fc-g Receptor Interaction
Desired Detrimental
Tumor-target driven T-cell activation NK mediated ADCC of T cells Non-tumor target driven random activation of T cells
T cell ADCC Activation
CD137
FcgR+
NK Cell T cell T cell
Killing cell
HER2
CD16 CD137 CD16 CD137 CD32
HER2+ tumor cell CD64
…
Desired mode of action is HER2-dependent CD137 clustering and activation on T cells Trastuzumab IgG1 backbone could induce undesired side effects of ADCC directed against T cells and non-tumor localized activation of T-cells via FcgR positive cells in the periphery
PRS-343 bispecifics contain trastuzumab with an engineered IgG4 backbone to minimize FcgR binding
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Engineered IgG4 Backbone Ensures Reduced FcgRI
& FcgRIII Interaction – FcRn Interaction Retained
FcgRI FcgRIII FcRn
Trastuzumab (IgG1)
Control fusion (IgG1) HC-C-Term. (IgG4engineered) LC-C-Term. (IgG4engineered) LC-N-Term. (IgG4engineered) HC-N-Term. (IgG4engineered)
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PoC: T Cell Activation by HER2-CD137
Bispecifics is HER2 Target-Dependent
Assay Design IL-2
IFN-g?
Costimulatory HER2 – CD137 T cell Bispecifics lead to activation
Activation
Excess of trastuzumab blocks Signal 1 Signal 2 binding of Bispecifics and T cell activation
a-CD3
antibody SKBR3 tumor cell
culture dish
Her-2 positive SKBR3 cells were grown on 96-well culture dishes, precoated with aCD3 antibody T cells from healthy donor PBMCs were added together with HER2—CD137 bispecifics to activate T cells Excess of trastuzumab inhibits binding of HER2 – CD137 bispecifics and activation of T cells
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PoC: T Cell Activation by HER2-CD137 Bispecifics is HER2 Target-Dependent
IL-2 response IL-2 response with Her2 blockade Assay design
Construct
A
Construct B
Activity is HER2 target+ dependent
Addition of excess trastuzumab
Construct Trastuzumab
prevents bispecific binding to
C
HER2-positive cells and results in a loss of activity
Geometry impacts activity of HER2-CD137 Bispecifics
Construct
D Three constructs are capable of activating T cells
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Pharmacokinetics of HER2-CD137 Bispecifics in Mice are Comparable to Trastuzumab
Pharmacokinetics in mice PK assay set up
trastuzumab
Construct A
detection Biotin titration coating
Bispecifics Trastuzumab
10mg/kg of bispecifics or trastuzumab were injected i.v. in male CD-1 mice (3 mice per timepoint) Terminal half-lives of bispecifics range from 15-21 days compared to 13 days for trastuzumab
Beneficial half-life of parental antibody is preserved for all bispecifics or even exceeded
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Summary and Path Forward
PRS-343: HER2-CD137 Bispecifics
– Exhibit excellent binding and drug-like properties with long half lives in mice
– Induce strong T cell activation via tumor target-dependent costimulatory T cell engagement
– Expected to allow potent local activation of tumor-specific T cells with low toxicity
PRS-343 Path to Clinic
– Drug candidate nomination planned for YE 2015
– Initiate IND enabling studies in 2016
– Aim to perform clinical trial in HER2-positive cancer in 2017
Pieris’ IO pipeline focusing on multiple targets
Pieris is pursuing both activating and inhibitory IO targets
Each immunomodulatory target combinable with different tumor targets
Bispecifics approach for tumor localized immune activation
Variable bispecific geometry facilitates optimal engagement for all receptors
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Pieris Pharmaceuticals, Inc.
255 State Street Boston, MA 02109 USA info@pieris.com
Pieris Pharmaceuticals, GmbH.
Lise-Meitner-Strasse 30 85354 Freising (Munich) Germany info@pieris.com
Thanks to the Pieris Team!
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