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IP Patentability/FTO assessment |
APPENDIX B |
Table 2: TRANSFERRED Materials to be shared from Capsida to Abbvie OR AbbVie to Capsida |
Below is a list of items that each Party may transfer to the other Party for use in the Research Program. These items may be transferred as physical samples, nucleotide/amino acid sequences or both. This is not a comprehensive list and may be modified based on needs for executing the Research Plan activities towards ac... |
Table 2: TRANSFERRED Materials to be shared from |
Item Description Comments |
CAPSIDA TO ABBVIE Rodent tool capsids (Existing capsids) (i) AAV.CAP-B10 (ii) AAV.CAP-B22 Sequences, materials |
Packaged with sequence optimized tool anti-tau cargo and tool anti-a-syn cargo |
Reserved Capsids _____ _____ _____ _____ Packaged with sequence optimized tool cargo, anti-tau cargo and /or anti-a-syn cargo |
ABBVIE TO CAPSIDA |
Table 3. CARGO Materials to be Transferred from AbbVie to Capsida |
Table 3: CARGO Materials to be Transferred from AbbVie to Capsida |
Item Description Comments |
Cargo β tau (i) Sequence for tool-anti-tau cargo (ii) Sequence for final anti-tau cargo Tool cargo at start of collab |
Final cargo est 4Q2021-1Q2022 |
Cargo β -synuclein (i) Sequence for tool-anti--syn cargo (ii) Sequence for final anti--syn cargo Tool cargo est 4Q2021 |
Final cargo est 4Q2022 |
Expression elements (i) expected regulatory elements As available |
Others |
Table 4. CAPSIDS AND RESEARCH PRODUCT MATERIALS - TAU PROGRAM |
Table 4: CAPSIDS AND RESEARCH PRODUCT MATERIALS - TAU PROGRAM |
Item Description Comments |
Reserved Capsids _____ _____ _____ _____ ______ as available |
Selected Capsids (Primary and Backup Capsids) _____ _____ _____ as available |
Research Product candidates (with tool or AbbVie cargo, including rodent versions) _____ _____ _____ _____ as available |
Research Product _____ as available |
Table 5. CAPSIDS AND RESEARCH PRODUCT MATERIALS: -SYNUCLEIN PROGRAM |
Table 5: CAPSIDS AND RESEARCH PRODUCT MATERIALS: -SYNUCLEIN PROGRAM |
Item Description Comments |
Reserved Capsids _____ _____ _____ _____ ______ as available |
Selected Capsids (Primary Capsid and Backup Capsids) _____ _____ _____ as available |
Research Product candidates (with tool or AbbVie cargo, including rodent versions) _____ _____ _____ _____ as available |
Research Product as available |
Exhibit B |
Collaboration Program Research Plan |
1.0 Background |
AbbVie and Capsida are collaborating on research activities aimed at identifying and optimizing capsids using the Capsida Platform to deliver the AbbVie Cargo ("cargo") to cells in the central nervous system and / or spinal cord. |
Capsida will harness its biologically driven, high-throughput non-human primate (NHP) screening platform and adeno-associated virus (AAV) engineering know-how to develop and validate novel AAVs with increased cargo expression and specificity for CNS cells (e.g., cortical neurons, dopaminergic neurons, oligodendrocytes)... |
2.0 Research Plan Scope and Framework |
AbbVie and Capsida have agreed to a Research Plan for the development of Capsid ("capsid") β cargo combinations for three targets: tau, Ξ±-synuclein and TDP43. This Research Plan (Collaboration Program Research Plan) outlines activities and estimated timelines to be conducted by Capsida or AbbVie, as specified below, fo... |
The Collaboration Program Research Plan will be focused on the generation of a fully characterized capsid β cargo combination for the TDP43 target. Capsida will be responsible for all activities within such plan as described in this document and in the Collaboration Program Research Plan Overview (Figure 2) below, with... |
Figure 2: Collaboration Program Research Plan Overview |
Figure 2: Collaboration Program Research Plan Overview |
3.0 Collaboration Program |
3.1 Initial Target Capsid Profile for TDP43 |
The overarching goal of the collaboration is to achieve a capsid profile with characteristics as outlined in Table 6 below aimed at delivering TDP43 cargo to relevant cell types in the CNS and spinal cord. The activities focus on the engineering of capsids directed towards a Target Capsid Profile for TDP43, which may b... |
Table 6. Initial Target Capsid Profile (TCP) for TDP43 Target |
Table 6: Initial Target Capsid Profile (TCP) for TDP43 Target |
TDP43 Capsid |
Targeted Cell Type* >80% transduction of motor neurons (upper motor neurons in the brain and lower motor neurons in the spinal cord) in the targeted tissue |
Targeted Tissue Cortex, Spinal cord |
Route of Administration IV route is required (with volume and titer feasible for IV dosing and consistent with FDA guidelines) |
Expression Level Equivalent or improved expression of RNA and / or protein as compared to efficacious expression levels observed in preclinical models using intraparenchymal or IV administration of reference capsids (e.g., AAV9, AAV.CAP-B10, AAV.CAP-B22) |
Tissue De-targeting >10-fold improved de-targeting of DRGs and liver (as compared to AAV9) |
Projected Human Dose Capsid-cargo combination safe in non-clinical safety studies in adult cynomolgus monkeys, providing an acceptable therapeutic window |
Manufacturing Improved packaging efficiency over AAV9 |
Immunogenicity Neutralizing antibody profile similar or better than AAV9 using industry standards |
IP Novel capsid β cargo combination for which IP can be filed |
*The desired percentage of transduction will be determined by the rodent efficacy studies. A lower transduction rate may be acceptable if supported by data from such studies; in such case, TCP may be amended as set forth in the Agreement. |
3.2 ALS Preclinical |
These activities will be led by Capsida, except for TDP43 cargo development which is AbbVie's responsibility (out of scope for this document). In addition, AbbVie will provide experimental support and scientific consultation to support execution of these studies. |
3.2.1 In vitro and In vivo models |
In vitro: Establish relevant biochemical and cellular assays to evaluate TDP43 biology. Characterization in neuronal / iPSC assays will be conducted unless otherwise determined by the Working Group. Expectation is to mimic rodent models by making the nuclear localization sequence defective in patient iPSC-derived neuro... |
In vivo: Establish relevant in vivo models to evaluate TDP43 pharmacology. In vivo studies will aim at relating dose- transduction efficiency β cargo expression β target engagement β TDP43 pathology. Preferred model is currently rNLS8 model expressing hTDP43 with defective nuclear localization signal, but other in vivo... |
3.2.2 Translational Biomarker Activities |
Develop a Translational / Biomarker data sets to advance TDP-43 program for ALS. (e.g., CSF, plasma biomarkers (expression, target engagement, pharmacodynamics etc.)) |
3.3 Capsid Engineering, Screening and Optimization |
Drug substance activities assume 3 parallel efforts: capsid engineering, vector optimization (e.g., promoter/ Gene Regulatory Elements (GRE)), and cargo development (out of scope for this document). |
All capsid engineering will be conducted by Capsida. There will be frequent and ad hoc communication and scientific dialogue between the Working Group while engineering is ongoing, gated by availability of relevant data. Per the governance framework, on a quarterly basis, the JGC will discuss and review available data ... |
3.3.1 Selection Process of New Capsids β TDP43 |
4.0 Initial Library Screening (6-months): |
Initial library screening efforts (i.e., de novo) begin with peptide substitutions and / or insertions and capsid variants are screened directly in 2-3 juvenile NHPs following an IV administration. Current and planned engineering efforts utilize 7-mer insertions after AA588 in AAV9, though Capsida will use all reasonab... |
Second-round screening will be conducted in 2-3 NHPs. The second-round library will contain AAV9, and any other characterized capsids (e.g., CAP-D1, etc.) as comparator benchmarks. Vector genome residence will be assessed using DNA sequencing in CNS cells and off-target tissues such as the liver and DRGs. In addition, ... |
Each of the two screening rounds in this Step #1 take 3-months to conduct, leading to a total period of 6-months. Five of the top performing variant capsids from this initial screening effort can be moved by AbbVie into Reserved Capsids and / or Pooled Screening, which decision may be made by the Working Group's determ... |
5.0 Variant Optimization (6-months): |
Top performing capsids from the Initial Library Screening will be moved into re-diversification and stabilizing library screening in 2-3 NHPs, aimed at increasing efficacy and / or specificity in CNS cells. Scanning (e.g., scanning 3-mer diversification) is currently being utilized for Variant Optimization purposes, th... |
Second-round screening of Variant Optimization libraries will be conducted in 2-3 NHPs. The second-round library will contain AAV9, and any other characterized capsids (e.g., CAP-D1, etc.) as benchmarks. Enrichment data will be read out at the DNA level in target tissues and off-target tissues such as the liver and DRG... |
Each of the two screening rounds during Step#2 take 3-months to conduct (total period of 6-months). Five capsid variants within the top performing capsids can be moved by AbbVie into Reserved Capsids and / or Pooled Screening, which decision may be made by the Working Group's determination that their fold-enrichment in... |
6.0 Pooled Screening (3-months): |
The top performing capsid variants from Initial Library Screening and from the Variant Optimization screening, including the 5 Reserved Capsids selected by AbbVie in the capsid selection process, will be tested in a small pooled screening experiment with a cargo (e.g., neutral cargo, tool TDP43 cargo or final TDP43 car... |
Five capsid variants within the top performing capsids from the Pooled Screening efforts can be moved by AbbVie into Reserved Capsids, which decision may be made by the Working Group's determination that their fold-enrichment in CNS cells versus off target tissues over benchmark comparator capsids meets TCP criteria. B... |
7.0 Preliminary Individual Capsid Characterization (6-months): |
Based upon the data package from capsid selection and pooled screening, AbbVie will decide whether there are capsids that meet or are sufficiently close to the desired TCP to proceed with Preliminary Capsid Characterization. |
AbbVie will select up to 3 capsid variants, preferentially representative of different capsid families for Preliminary Capsid Characterization in 3 NHPs and in rodents when applicable. The final study design will be determined by the Working Group considering the inclusion of up to 3 capsids preferentially from differe... |
8.0 Final Capsid Optimization (6-months): |
In parallel with Preliminary Capsid Characterization, unless otherwise determined by the JGC, Capsida will perform final capsid optimization, screening (6 months) and pooled screening (3 months) prior to Final Individual Cargo - Capsid Characterization. Further capsid optimization and screening involves re-differentiat... |
9.0 Final Pooled Screening (3-months; Activities similar to Step 3): |
The top performing variants from the Final Capsid Optimization screening, including any variants previously reserved by AbbVie during the capsid selection process would be moved into Pooled Screening, These capsid variants will be tested in a small pooled screening experiment with a cargo (e.g., neutral cargo, tool TDP... |
The collective data generated during the Final Capsid Optimization (Step#5) and the subsequent Pooled Screening (Step#6), in combination with the data generated from the Preliminary Characterization (Step#4) will inform AbbVie's decision on the selection of a Primary Capsid and two Back-Up Capsids. The Primary Capsid w... |
10.0 Final Individual Capsid β Cargo Characterization (6-months): |
Based upon the data package from capsid selection, pooled screening, and upon selection of a final cargo vector design, AbbVie will select a single variant (i.e., Primary Capsid) to carry forward for Final Individual Capsid β Cargo Characterization in up to 6 NHPs and rodents with AbbVie cargo. Capsida will perform a b... |
The final data package for the Primary Capsid selected for Final Individual Capsid - Cargo Characterization will be based on the collective data package across capsid engineering, cargo development and optimization, and disease efficacy studies with an ultimate objective of defining a therapeutic window that is satisfa... |
All screening and pooled testing steps will be done in juvenile NHPs, as well as the preliminary capsid characterization. The stage at which the capsid -- cargo pairing can be characterized in adults is the final characterization stage; the Working Group will decide on the age range, depending on animal availability. |
10.1.1 Mechanics of Capsid Variant Selection Process |
In advance of the JGC meetings, Capsida will aggregate and prepare all relevant available data, based on stage of engineering, including library screening and/or pooled screening data, as summarized in Appendix 6. This summary will include rationale for sequence modifications and based on available datasets, the relati... |
In order to track the top performing capsids, Capsida will maintain an excel spreadsheet which documents and identifies the top performing capsids. This tracker will be reviewed as standard part of agenda at JGC meetings and memorialized in the meeting minutes. The tracker can be stored on a shared file server and made... |
10.2 TDP43 Capsid β Cargo Characterization |
10.2.1 TDP43 Cargo Development |
AbbVie is developing a tool TDP43 cargo and the final TDP43 cargo, which activities are outside the scope of the research plans. The tool TDP43 cargo will be verified in solubility and target-engagement assays before transferring to Capsida. Using this tool TDP43 cargo, AbbVie and Capsida jointly will design a vector o... |
10.2.2 Dose β Efficacy Relationship Studies in Mice |
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