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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 |
In vivo dose frequency study |
In vivo MED/ MABEL study |
Definitive mouse model (hybrid pharm/tox) |
In vivo histopathology model |
GLP toxicology study (NHP) |
Bioanalytical for Phase I & Reagent Generation |
Switch CMC support |
INTERACT meeting |
Pre-IND meeting |
Phase I readiness KOL and potential PI interactions |
Phase I clinical synopsis generation |
Phase I clinical CRO budget estimates / quotes & negotiations |
Phase I Minaris scope negotiations / quotes for recontracting |
IND preparation & report writing |
2. CMC Support |
Key assumptions: Calibr will carry out studies to establish the feasibility of initiating a CLBR001 manufacturing process from cryopreserved apheresis. If successful, and able to be implemented prior to IND, this method may be included in the process run by Minaris for the Phase I study. |
Component Activities |
Lentivirus Comparability Studies |
Cryo method development |
Schedule 2.3.2-a: mRNA Work Plan |
[See attached.] |
CONFIDENTIAL 2.3.2-a-1 |
MRNA WORK PLAN 2023-2025 |
This Work Plan summarizes the activities and deliverables to develop sCAR-T Switch dosing modalities such as, mRNA-based, to deliver switch to subjects who have received CLBR001 switchable CAR-T cells. Calibr, A Division of Scripps Research will carry out the work in conjunction with appropriate CDMOs. |
Work Plan |
Period Covered |
Deliverable |
Background |
Improving dosing regimens is important to reducing burden on patients, increasing patient compliance, and improving the commercial feasibility of the sCAR-T cell platform. As outlined in slides presented to AbbVie leadership on Feb 3rd, 2023, there are multiple options to reduce dosing burden. Of these options, mRNA is... |
Component Activities |
Discovery |
(a) Conduct discovery and feasibility activities for mRNA-liquid nanoparticle (mRNA-LNP) delivery approach |
a. Establish acceptance criteria for preclinical and draft clinical target profile |
i. The initial desired profile of the mRNA-LNP will target a once-monthly dosing, comprising approximately 7 days of exposure of the switch molecule followed by 21 days of no exposure. The target route of administration (ROA) is intravenous |
(IV), although other ROAs may be evaluated. This is similar to the current sCAR19 clinical dosing regimen with SWI019 Fab. Other profiles may be generated and compared. |
b. Identify CDMO for (i) R&D-scale plasmid and mRNA material, (ii) clinical-scale material, and (iii) LNP formulation. The CDMO may be the same or may be different for each requirement. |
(b) Design mRNA for expression of switch. Sequences for the anti-CD19 switch SWI019 or anti-Her2 switch are expected to be used initially for proof of concept. Design will include input from consultants and KOLs. Multiple iterations of design and production are expected to generate a library of sequences including the ... |
a. Determine use of 5' capping technology |
b. Identify appropriate 5' and 3' UTR sequences |
c. Generate codon-optimized mRNA coding sequence |
d. Identify suitable plasmid to harbor components |
e. Identify appropriate signal peptide (leader sequences) |
f. Identify suitable LNP formulations for proof of concept. Multiple LNP formulations may be used to study cell tropism |
(c) Generate LNP-mRNA for R&D scale |
a. Initial CDMO's identified with such capabilities are Trilink, Curia, and Etherna. Other CDMOs may be used, including for the generation of plasmid DNA. |
(d) Characterize LNP-mRNA at the R&D scale. R&D scale will be sufficient for in vitro and in vivo proof of concept studies. |
a. Determine that LNP-mRNA meets established acceptance criteria via analytical testing |
(e) Characterize switch protein production and activity in vitro |
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