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sCAR-T + Switch: In vitro activity profiling (dose-dependence) Chevron 4 In vitro activity on selected candidates to be demonstrated dose dependent on antigen-positive cells. Selectivity index (SI) between antigen positive and antigen-negative tumor cell line to be determined. Calibr to deliver data package which inclu... |
Switch: Protein characterization/ profiling (R&D) Chevron 5 Biophysical characterization of 9 selected candidates to occur simultaneously with sCAR-T + Switch in vitro activity profiling Biophysical characterization of 9 selected candidates to occur simultaneously with sCAR-T + Switch in vitro activity profiling. AbbVi... |
sCAR-T + Switch: In vitro activity profiling (healthy tissue/cell line panel) Chevron 6A In vitro activity on 3 prioritized candidate switches to be demonstrated in dose dependent format on healthy tissue derived cells. Selectivity index (SI) between antigen positive and healthy tissue derived cells line to be determin... |
In vivo efficacy assessment in NSG mice (single switch) Chevron 6B Assess in vivo activity of sCAR-T + prioritized 3 Switches individually in appropritate xenograft tumor model setting including nontransduced T cells and sCAR-T with irrelevant control switch (SWI019). Demonstrate reduction of tumor burden in NSG (immun... |
In vivo efficacy assessment in NSG mice (dual switch). Chevron 7 Assess in vivo activity of sCAR-T + two candidate Fab switches targeting different antigens in a single in vivo xenograft model model. Model parameters, benchmaks, and controls to be similar to above. Analyses to follow parameters outlined above. AbbVie t... |
Lead Fab switch selection and manufacture and in vitro validation of materials for additional studies Chevron 8 Selection of one prioritized candidate Fab switch sequence for each tumor antigen targets (2 Fab switches total). Sufficient candidate and control Fab switch protein expression and purification sCAR-T transdu... |
In vivo efficacy in Xeno model in NSG mice to support IND (Definitive mouse model aka GLP/ GLP-like model) Chevron 9 Assess in vivo activity of sCAR-T with Fab switches in appropriate preclinical efficacy model to support IND package Efficacy analysis of sCAR-T to support IND pacakage Calibr to design and conduct effic... |
Confirmatory in vivo efficacy assessment in PDX tumor model in NOD Scid Mice Chevron C Assess in vivo activity of lead sCAR-T + Switch in appropritate PDx tumor model setting including untransduced T cells and sCAR-T with irrelevant control switch (SWI019). Demonstrate reduction of tumor burden in NOD Scid (immunodefic... |
Transgene knockdown sCAR-T (shRNA knockdown sCAR-T) Component Activities Requirements Deliverables Responsible Timeframe TD-JRC |
Base Materials Chevron 10 sCAR-T and Herceptin Fab switch will be used as a platform base for work flow activities Calibr 1 month |
Production and testing of optimizing shRNAs for transgene removal Chevron 10 shRNA sequence confirmation of transgene removal/knockdown on T cells (5 shRNA per target) of up to 3 target genes Calibr/AbbVie to identify 3 genes for knockdown with putative impact on activity, memory, persistence, or resistance to immunosu... |
shRNA-sCAR-T sub-cloning Chevron 10 Sub cloning of the candidate shRNA sequences to Calibr's previously constructed sCAR-T vector, harboring the mu6 shRNA promoter and cloning site Calibr to provide sequence confirmation of each of the 15 candidates and controls (Luc-based shRNAs – already made at Calibr). Calibr 2 mon... |
Transduction of armoured sCAR-T Chevron 11 Demonstration of T cell transfection and expression of sCAR-T and shRNA Data confirmation of sCAR-T expression, shRNA expression. Calibr to provide data and results confirming sCAR-T and shRNA expression. 4 months |
In vitro phenotypic and functional characterization Chevron 12 Confirmation of sCAR-T expression and transgene knockdown on transduced T cells and in vitro functional analysis Confirmation of T cell transduction and T cell phenotype analysis In vitro assay activity data to be generated using Target Antigen (Ag) +/- cel... |
In vivo efficacy assessment in NSG mice Chevron 13 Assess in vivo activity of standard sCAR-T compared to transgene knockdown sCAR-T in appropriate preclinical efficacy model Efficacy analysis of standard sCAR-T compared to armoured sCAR-T Calibr and AbbVie to design efficacy studies. Calibr to deliver results and data... |
In vitro efficacy and surrogate safety biomarker in syngeneic animals Chevron 14 Repeat in vitro development in mouse background on a single target candidate with up to 5 shRNA – necessary to measure benefit of DNR construct in competent immune system Repeat in vitro development, can overlap with human system Calibr op... |
In vivo efficacy assessment in surrogate mice Chevron 15 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate syngeneic model Efficacy AbbVie to deliver data and results to Calibr 6 months (depending upon models chosen) |
Dominant Negative Receptor (DNR) sCAR-T Selection of DNRs Chevron 16 Up to 3 DNRs to be tested. Calibr/AbbVie to identify candidate TME sequences and background data/rationale and any confirmatory or preliminary studies on 3 DNRs to be tested in the Calibr sCAR-T platform. Include FTO analysis (this may be waived with ... |
DNR sCAR-T sub-cloning Chevron 16 Subcloning of the 3 DNR genes into a bicistronic lentiviral transfer vector harboring the sCAR-T. Calibr to provide AbbVie with sequence confirmation of 3 DNR genes in up to 2 formats (T2A and IRES) with the sCAR-T lentiviral transfer vector – up to 6 constructs Calibr 3 months |
Transduction of armoured sCAR-T Chevron 17 Demonstration of T cell transfection and expression of sCAR-T and dominant negative receptor Data confirmation of sCAR-T expression, dominant negative receptor expression Calibr to provide data and results confirming sCAR-T and dominant negative receptor expression 2 months |
Phenotypic and functional characterization Chevron 18 Confirmation of sCAR-T expression and dominant negative receptor expression on transduced T cells and in vitro functional assessment Confirmation of T cell transduction T cell phenotype analysis. In vitro assay activity data to be generated using Target Antigen (Ag)... |
In vivo efficacy assessment in NSG mice Chevron 19 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate efficacy model Efficacy Calibr to deliver data and results to AbbVie. 8 months (depending upon models chosen) |
In vitro efficacy and surrogate safety biomarker in syngeneic animals Chevron 20 Repeat in vitro development in mouse background with a single DNA candidate – necessary to measure benefit of DNR construct in competent immune system Repeat in vitro development, can overlap with human system Calibr to design murine react... |
In vivo efficacy assessment in syngeneic model mice Chevron 21 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate efficacy model. Efficacy Calibr to deliver data and results to AbbVie. 6 months (depending upon models chosen) |
Tumor Microenvironment Armoured sCAR-Ts Selection of TME armoured transgenes Chevron 22 Up to 3 TME transgenes to be tested – inducible vs non-inducible (NFAT) promoters to be discussed based on nature of target TME transgenes. Joint Research Committee may choose to nominate all armoured options in this category and as... |
Subcloning & expression of transgene Chevron 22 Subcloning of the chosen TME transgenes into a bicistronic lentiviral transfer vector harboring the sCAR-T. Calibr to provide AbbVie with sequence confirmation of TME transgenes in up to 2 formats (inducible vs non-inducible) with the sCAR-T lentiviral transfer vector Cal... |
Transduction of peripheral blood production of armoured sCAR-T Chevron 23 Demonstration of T cell transfection and expression of sCAR-T and tumor microenvironment transgene Data confirmation of sCAR-T expression, tumor microenvironment transgene expression Calibr to provide data and results confirming sCAR-T and transg... |
Phenotypic and functional characterization Chevron 24 Confirmation of sCAR-T expression and transgene expression on transduced T cells and in vitro functional assessment Confirmation of T cell transduction (sCAR-T expression and transgene expression) T cell phenotype analysis In vitro assay activity data to be generate... |
In vivo efficacy assessment in NSG mice Chevron 25 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate efficacy model Efficacy Calibr to deliver data and results to AbbVie 8 months (depending upon models chosen) |
In vitro efficacy and surrogate safety biomarker in syngeneic animals Chevron 26 Repeat in vitro develoment in mouse background – necessary to measure benefit of transgene construct Repeat in vitro development, can overlap with human system Cablir to design murine reactive switch or to obtain human Her2 transgeneic mou... |
In vivo efficacy assessment in syngeneic mice Chevron 27 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate efficacy model Efficacy Calibr to deliver data and results to Abbvie 6 months (depending upon models chosen) |
2. sTCR Switch sCAR-T Workflow (Gantt – "Proposed Discovery sTCR Switch sCAR-T Workplan") a. Standard Platform |
Component Activities Requirements Data Deliverables Comments Timeframe TD-JRC |
Transfer of soluble TCR Sequences Chevron A One control soluble TCR sequence and 3-6 candidate soluble TCR sequences with a range of binding affinities AbbVie: TCR sequences and evidence of target binding and affinities AbbVie to deliver Control TCR sequence and one candidate TCR sequence with MHC binding data to be de... |
Design of sTCR switch format library with control and first candidate TCRs Chevron 1 Switch grafting designs to be established for soluble TCR-based switches (each format, domain orientation, and peptide grafting location is considered a design candidate) using a control and the first candidate TCR Calibr to design can... |
Production of sTCR switch proteins based on control and first candidate TCRs Chevron 2 sTCR switch grafting designs (each format and peptide grafting location is considered a design candidate) based on control and first candidate TCR to be tested for expression Calibr to express sufficient quantity for in vitro activit... |
sCAR-T + sTCR Switch: In vitro activity screen of sTCR switches based on control and first candidate TCR Chevron 3 In vitro evaluation to test the functional activity of each candidate TCR switch protein in the presence of T2 target cells loaded with cognate peptide an irrelevant peptide. 3 independent human T cell don... |
Design of sTCR switch format library with additional candidate TCRs Chevron 4 Up to 3 switch grafting designs (each format, domain orientation and peptide grafting location is considered a design candidate), where selected designs are guided by control TCR expression and activity results) per TCR sequence Calibr to des... |
Production of sTCR switch proteins based on additional candidate TCRs Chevron 5 sTCR switch grafting designs (each format and peptide grafting location is considered a design candidate) based on additional candidate TCRs to be tested for expression Calibr to express sufficient quantity for in vitro activity screen (bel... |
sCAR-T + sTCR Switch: In vitro activity screen of sTCR switch proteins based on additional candidate TCRs Chevron 6 In vitro evaluation to test the functional activity of each switch in the presence of antigen-positive vs. antigen-negative target cells. 3 independent human T cell donors/construct will be used to genera... |
sCAR-T + sTCR Switch: In vitro activity profiling with healthy tissue/cell line panel Chevron 7 In vitro activity on 3 prioritized candidate switches to be demonstrated in dose dependent format on HLA allele-matched healthy tissue derived cells. Selectivity index (SI) between antigen positive and healthy tissue derived... |
In vivo sCAR-T + sTCR switch efficacy assessment in NSG mice Chevron 8 Assess in vivo activity of sCAR-T + prioritized 3 candidate sTCR switches in appropritate Xeno tumor model setting including nontransduced T cells and sCAR-T with control sTCR switch. Demonstrate reduction of tumor burden in NSG (immunodeficient) mi... |
Lead sTCR switch selection, manufacture and in vitro validation of materials for hand off to AbbVie for PDX model in Chevron 9 Selection of one prioritized candidate sTCR switch sequence. Sufficient candidate and control sTCR switch protein expression and purification sCAR-T transduction vector, and transduced, frozen ... |
In vivo efficacy in Xeno model in NSG mice to support IND (Definitive mouse model aka GLP/ GLP-like model) Chevron 13 Assess in vivo activity of sCAR-T and sTCR switch in appropriate preclinical efficacy model to support IND package Efficacy analysis of sCAR-T to support IND pacakage Calibr to design efficacy studies i... |
Confirmatory In vivo efficacy assessment in PDX/Xeno tumor model in NOD Scid Mice Chevron B Assess in vivo activity of sCAR-T cells + lead sTCR swtich in appropritate PDx/Xeno tumor model setting including untransduced T cells and sCAR-T with irrelevant control switch. Demonstrate reduction of tumor burden in NOD Scid ... |
Component Activities Requirements Deliverables Responsible Timeframe FTE |
Armoured sTCR Switch sCAR-T Chevron 10 Work plan will utilze platform base determined from armoured Fab Switch sCAR-T work plan Calibr 1 month |
Lead selection, manufacture, and in vitro validation to support armoured sTCR Switch sCAR-T in vivo work Chevron 11 Confirmation of Armoured sCAR-T expression on transduced T cells, prioritized sTCR switch sequence, and in vitro functional analysis. Confirmation of transgene expression. Calibr to generate in vitro assa... |
In vivo efficacy assessment of Armoured sTCR Switch sCAR-T in NSG mice Chevron 12 Assess in vivo activity of armoured sCAR-T versus standard platform sCAR-T in appropriate efficacy model with lead sTCR switch Efficacy Calibr to deliver data and results to AbbVie 6-8 months (depending upon models chosen) |
3. CMC/manufacturing/cell production activities that apply to all above platforms (Gantt – "Fab Switch sCAR-T Preliminary CMC/Manufacturing Plan" and "sTCR Switch sCAR-T Preliminary CMC/Manufacturing Plan") All contracts with vendors to be written such that AbbVie is enabled as the sponsor of clinical trial. |
Component Activities Requirements Data Deliverables Responsible Timeframe TD-JRC |
Switch Production for pre-IND and IND CMC CMC Chevron D Development of formulation and manufacturing process, analytical testing and safety assessment for peptide(s) (Fab switch) per Agency requests. Manufacturing, testing, release and stability. Quality Oversight Label, ship, storage, etc. DMF documentation. Documenta... |
Lentivirus Vector Construct,CMC development, and manufacturing: Tech transfer to CMO & process and methods development CMC Chevron E Technical transfer of transgene sequence. Process development, analytical development. Manufacture material for Safety studies and Cell process development and demonstration. Manufacture ... |
c. sCAR-T cell Process Development. Cell Production at CMO for IND CMC Chevron F Process development, analytical development and demonstration of robustness, reproducibility. Manufacturing, Release, Label, ship, storage, etc. Development of processes for cell collection, cell processing, cell culture, cell harvest, cry... |
4. GLP Tox Study (All Platforms) (CMC Chevron G) |
Component Activities Requirements Deliverables Responsible Timeframe TD-JRC |
IND enabling GLP Toxicology Study: A GLP study (or studies) in non-tumor bearing animals as guided by input from the FDA to assess the safety universal sCAR-T and Switches will be conducted in the appropriate/ designated preclinical species. CMC Chevron G Exact study design TBD and will be based on prior preclinical da... |
Additional GLP studies requested by Agency Should the agency request additional studies not included in the workplan, both parties will decide how to split responsibilities. AbbVie/Calibr If specific tumor bearing mouse models are requested by the agency, then the party that conducted the initial studies in requested m... |
5. Documentation Deliverables per Program (CMC Chevron H)– Scope Across All Target/Technology Combinations |
Component Activities Requirements Deliverables Responsible Timeframe TD-JRC |
Structure of sCAR-T and Switch Graphical and written descriptions of sCAR-T and Switch PreIND/IND section – description Calibr |
Structure of Target/s or "Armours" – Transgene additions and/or deletions Graphical and written descriptions of targets and payloads PreIND/IND section – description Calibr/AbbVie |
Characterization of Technology: sCAR-T and/or Fab or sTCR Switches; Armoured sCAR-Ts and/or Fab or sTCR Switches Sequence of insert Vector Description/Map IND section – description Calibr/AbbVie |
Technology: Transduction and Expression Characterization (Flow Cytometry) Assessment of "Technology" expression in CD3+ T cells by Flow cytometry: Control will be Technology appropriate compared to "Technology" Target-specific expression (anti-Id or peptide-fluor required) CD3 plus scFv positivity; appropriate isotype ... |
Technology: Transduction and Expression Characterization (Western Blot) Assessment of "Technology" expression in CD3+ T cells by Western Blot: Control will be Technology appropriate Compared to "Technology" Target-specific expression Anti-CD3ζ or technology domain (41BB/CD28, etc) specific western blot applicable antib... |
Kinetics of Numeric Expansion of Technology Specific Recombinant T cells Absolute and fold expansion of total T cell populations from untransduced and "technology"-transduced T cells, following CD3/CD28 stimulation (TBD Beads or TransAct) Expansion data will be captured from 3 donors reported as mean +/- SEM on plot IN... |
Copy Number Assessment of "Technology" Specific T cells Following Lentiviral Transduction qPCR (qPCR) will be used to determine the number of transgene copies integrated into the T cell genome following lentiviral transduction. Assay will be carried out using the following sample: Untransduced – T cells Transduced – Ir... |
Target Specificity and in vitro Cytotoxicity of "Technology" Recombinant T cells Technology-specific cytotoxicity will be measured using "Target"-negative and -positive cells lines as well as disease-specific cells line where applicable. Target/Antigen-specific expression on all cell lines will be demonstrated using fl... |
Target-Specific Cytokine Production from ex vivo expanded "Technology" recombinant T cells An assessment of cytokine and payload (where applicable) production from non-transduced and transduced "Technology" recombinant T cells (3 independent human donors) following co-culture with various disease-specific cell lines wh... |
NSG Mouse Xenograft In Vivo Tumor Model Development: Base Model For antigen-specific tumor xenograft kinetics study, 1 "Target" antigen-positive cell line will be assessed in vivo using tbd dose levels of switches (for example low, medium and high). The tumor line will be a cell line provided by AbbVie to express the t... |
NSG Mouse Xenograft In Vivo Tumor Model Development: Switch Peptide PK Assessment Switch doses (No T cells) will be administered to the mice at concentrations reflecting the expected normal distribution in human patients as reported in the literature and determined from internal data assessing model-specific drug conce... |
NSG Mouse Xenograft In Vivo Tumor Model Development: Switch Assessment For antigen-specific tumor, 1 "Target" tumor cell line will be assessed in vitro for expression of target and cytotoxic activity in the presence of the sCAR-T cell and Switch. Model development will include administration of a negative control switc... |
NSG Mouse Xenograft In Vivo Tumor Model Development: Armoured sCAR-T For antigen-specific tumor, 1 "Target" tumor cell line will be assessed for expression of tumor target antigen. sCAR-Ts with and without payload will be generated for in vivo model assessment. Model development will include in vivo characterization us... |
NSG Mouse Xenograft In Vivo Tumor Model Development: Analytical Assessment In all tumor models the following analytical parameters will be performed: Pre-dose assessment of "Technology" recombinant T cells: 1. Cells % Transduction by flow cytometry – "Technology antigen"- surface expression targeted by Fab switch or sT... |
"Technology"-Specific Recombinant T cell Release Assays for GLP or "GLP-like" definitive Mouse Studies Safety 1. Sterility 2. Mycoplasma 3. Endotoxin 4. Recombinant Lentivirus 5. Copies of transgene insertion (<4 copies/T cell) Purity 1. Percent CD3+ T cells 2. Percent Technology+ T cells (detection by anti-Id or Tetra... |
CMC documentation per program CMC reports, data and records that describe process / method development. Records pertaining to GMP manufacture, testing, and lot release CTD sections and CMC reports, including letters of cross reference to BMFs AbbVie to be responsible for GMP CMC to enable IND. Calibr to provide documen... |
ABBREVIATIONS: sCAR-T: Switchable Chimeric Antigen Receptor T cell mRNA: Messenger RNA scFv: single-chain variable fragment ECD: extracellular domain CSFE: Carboxyfluorescein succinimidyl ester Ag: Antigen VL: Variable domain, Light Chain VH: Variable domain, Heavy Chain FACS: Fluorescence-activated cell sorting GFP: G... |
TransAct: T cell Stimulatory Reagent SEM: Standard Error of the Mean PCR: Polymerase Chain Reaction SD: Standard Deviation LC-MS/MS: Liquid chromatography–mass spectrometry/mass spectrometry %F: Bioavailability T1/2: Half-life AUC: Area Under the Curve ELISA: enzyme-linked immunosorbent assay TCM: Central Memory T cell... |
ϭ͘Ϯϳϯ – 4Ϯ |
Gantt Charts: |
ϭ͘Ϯϳϯ – 4ϯ |
ϭ͘Ϯϳϯ – 4ϰ |
ϭ͘Ϯϳϯ – 4ϱ |
ϭ͘Ϯϳϯ – 4ϲ |
Target Research Plan Budget: |
Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 FTE Number 8 12 18 18 18 18 18 18 18 18 18 18 18 18 18 18 12 8 FTE budget 630,000$ 945,000$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 1,417,500$ 945,000$ 630,000$ Ou... |
2018 2019 2020 2021 2022 |
Schedule 1.273(a): PRLR Interim Research Plan |
[See attached.] |
1.2ϳϯ(a)-1 CONFIDENTIAL |
PRLR INTERIM RESEARCH PLAN |
All work will be governed by the AbbVie-Calibr JGC, pursuant to the Amended and Restated License Agreement between AbbVie and the Scripps Research Institute (Calibr). The work plan covers activities up to Q2 2024. |
1. PRLR Activities Key assumptions in work plan: |
Preclinical: Calibr will carry out all activities related to IND-enabling studies and hold interactions with the FDA and AbbVie as appropriate. Calibr will be Sponsor for the PRLR IND. Regulatory interactions are expected to include INTERACT meeting, pre-IND, and ad hoc specific questions and interactions. The specific... |
Clinical: The IND is expected to be a single IND for CLBR001 and a PRLR-directed Switch with protocol design as a first in human dose escalation study of PRLR Switch in patients to identify the MTD or RP2D. The target patient population (e.g., breast cancer or basket trial), inclusion criteria (PRLR status inclusion cr... |
Switch manufacture: AbbVie CMC is expected to complete and have available for Calibr use: R&D material by April 2023; tox batch by September 2023; DS (aliquots) by April 2024; DP filled by May 2024. AbbVie will complete manufacture and stability studies on PRLR-directed Switch. |
CLBR001 cell mfg: Calibr, with AbbVie's support, will manage cell manufacturing for CLBR001 for the PRLR Phase I trial. AbbVie will transfer lentivirus manufactured at Lentigento Minaris and will maintain responsibility for bearing the cost and maintenance of lenti stability studies. AbbVie will terminate the contract ... |
for CLBR001 DP. AbbVie will maintain contract with Minaris for sufficient time to allow continuity of the program, which will include funding activities under current scope of work at Minaris while Calibr negotiates new scope and contract. This is expected to require 4 months (through Oct 2023). AbbVie will approve the... |
Component Activities |
In vitro potency testing |
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