Avacta Group Plc · LSE:AVCT
Avacta — Immunotherapy World Congress 2021
21 slides from Avacta's conference presentation, November 2021
Slide 1: FAP-Activated Drugs and Drug-Conjugates
FAP-Activated Drugs and Drug-Conjugates Immunotherapy World Congress – November 2021 IWC 2021 - Avacta Presentation
Slide 2: Disclaimer: Important Notice
Disclaimer: Important Notice No representation or warranty, expressed or implied, is made or given by or on behalf of Avacta Group plc (the “Company” and, together with its subsidiaries and subsidiary undertakings, the “Group”) or any of its directors or any other person as to the accuracy, complete
Slide 3: Our Therapeutic Strategy - Targeting Cold Tumours
Our Therapeutic Strategy - Targeting Cold Tumours 100aa (14kd) single domain antibody mimetic Small Molecule Prodrugs Selectively Activated by Macromolecular-Drug Conjugates Selectively with superior biophysical properties FAP upregulation in Tumour Microenvironment Activated by FAP in Tumour Microe
Slide 4: Fibroblast Activation Protein-α (FAPα) as a Tumor Target
Fibroblast Activation Protein-α (FAPα) as a Tumor Target FAPα is selectively overexpressed and FAPα enzymatic activity is elevated in the tumour microenvironment of most solid tumours 68Ga-FAPI-04 Tracer uptake in tumous Expression profiles of FAPα in normal and malignant human epithelial tissues –
Slide 5: FAP Activated pre|CISION and TMAC Prodrugs
FAP Activated pre|CISION and TMAC Prodrugs Proprietary Prodrug Platform Relies on Extracellular FAPα Enzyme Activity The overexpression of FAPα on the surface stromal cells of human tumors (relative to normal tissue) provides the premise for the development of prodrugs that remain inert until specif
Slide 6: AVA6000 – FAPα-Activated Doxorubicin pre|CISION Prodrug
AVA6000 – FAPα-Activated Doxorubicin pre|CISION Prodrug Why start with Doxorubicin? In practice, cardiotoxicity creates limits to patient Because of its Effects Beyond Direct Toxicity to Cancer Cells exposure below maximum effective concentration pivotal contribution of both innate and adaptive immu
Slide 7: Begins with A Proprietary and Selective FAPα Substrate Moiety
Begins with A Proprietary and Selective FAPα Substrate Moiety Based on natural substrate specificity, the field has focused on Gly-Pro for creating FAP-targeting and FAP-activated prodrugs FAP is a cell surface protein, meaning its protease activity is located in the extracellular space of the tumor
Slide 8: Post-Proline Cleaving Enzymes
Proprietary FAPa Substrate is key to pre|CISION prodrugs and TMAC Post-Proline Cleaving Enzymes See Huang et al. J Drug Target. 2011;19(7):487–496c Z-GP-DOX P’1 P2 P1 Proline and daunosamine (D) ring of DOX fulfill the P1 and P’1 specificity of FAP - but glycine Glycine in P2 position is not specifi
Slide 9: Cleavage of pre|CISION Substrate is Very Tightly Controlled for FAPα-selective Activation
Cleavage of pre|CISION Substrate is Very Tightly Controlled for FAPα-selective Activation Normal mouse muscle lysate catalyzes the release of Indicates some enzyme(s) beyond FAPα doxorubicin from Z-GP-DOX, but not from AVA6000 activate Z-GP-DOX but not AVA6000 Z-Gly-Pro-DOX Doxorubicin released from
Slide 10: Summary of Early Safety Information - Non-clinical Studies
Summary of Early Safety Information - Non-clinical Studies AVA6000 Prodrug is Not Cell Permeable so is Excluded from the MOA site of Doxorubicin Intracellular Doxorubicin (released from prodrug) [doxorubicin] in cells (µm) Intracellular AVA6000 prodrug In vitro monolayer cultures of either HEK cells
Slide 11: AVA6000 - Doxorubicin Selectively Delivered to Tumour Relative to Cardiac Tissue
AVA6000 - Doxorubicin Selectively Delivered to Tumour Relative to Cardiac Tissue Tissue levels (AUC15-45 mins) of doxorubicin in HEK-mFAP-tumor bearing mice following a single intravenous dose of doxorubicin or AVA6000 Slide | 11
Slide 12: Metastatic Sites Also Overexpress FAPα Relative to Site Tissue
Metastatic Sites Also Overexpress FAPα Relative to Site Tissue Expression profiles of FAPα in normal and malignant human epithelial tissues. AVA6000 Reduces Colorectal Cancer (CRC) Liver Metastasis Normal (green), malignant (red), and malignant metastatic lesions (orange) • Tumour cells derived from
Slide 13: TME-Activated Drug Conjugates Promote Immune Infiltration
TME-Activated Drug Conjugates Promote Immune Infiltration Traditional ADCs TMAC FAP-selective linker releases drug moiety in the extracellular space of tumour cell destruction • Drug moiety is selected to create local inflammatory response, degrade tumour stroma, promote immune cell infiltration a
Slide 14: Modular Design Enabled: Exemplars
Modular Design Enabled : Exemplars Linking Chemistry + Spacer Enzyme Cleavage Site Optional: self immolative linker Drug Moiety I-DASH Inhibitor B(OH)2 FAP substrate TRL7/8 Agonist MMP2 substrate STING Agonist Legumain substrate • Hydrocarbon to polyethers (like • Extracellular Enzyme Substrate • Ca
Slide 15: I-DASH Inhibitors - Induce Broad T-cell Activation and Enhance Recruitment
I-DASH Inhibitors - Induce Broad T-cell Activation and Enhance Recruitment of Elements of the Innate Immune System. I-DASH Inhibitors Direct and Indirect Effects* Immunostimulatory Cytokines Intratumoural CXCL10 Half-life anti-CTLA-4 Dendritic Cell Trafficking Adapted from Chen and Mellman 2013, Imm
Slide 16: Drafting on Clinical Experiences… Solving for Systemic Toxicity
Drafting on Clinical Experiences… Solving for Systemic Toxicity that produce the DLTs Point Therapeutics brought Talabostat (Val-boroPro) to Phase 3 for oncology indications without understanding the true MOA (macrophage pyroptosis) – and without understanding the true IO potential of the I-DASH inh
Slide 17: Talabostat turns out to have been a near miss
Talabostat turns out to have been a near miss …. due to dose de-escalation after Phase 1 Phase II assessment of Talabostat and Phase II assessment of Talabostat in cisplatin in second-line stage IV melanoma metastatic colorectal cancer Commencement of Talabostat Therapy Phase II, open label, single
Slide 18: Talabostat turns out to have been a near miss
Talabostat turns out to have been a near miss …. due to dose de-escalation after Phase 1 Phase I In FAP+ tumor burdened models, various FAP-activated TMAC formats can achieve intratumoral concentrations Pyroptosis is the MOA for greater than 100nM Val- Talabostat’s anticancer activity 100nM boroPro
Slide 19: TMAC Conjugates Selectively Deliver Activated Drug Moiety to Tumour
TMAC Conjugates Selectively Deliver Activated Drug Moiety to Tumour with Low Systemic Exposure and for Sustained Periods of Time Note: Val-boroPro is the active ingredient in Talabostat, and selectively induces macrophage pyroptosis, which in the tumor causes induction of both innate and adaptive re
Slide 20: TMAC Conjugate Has Pronounced Safety Improvement over Talabostat
TMAC Conjugate Has Pronounced Safety Improvement over Talabostat This dose of Parent Drug produces inhibition of tumor growth in ~50% of mice, but not full regression Val-boroPro TMAC format is better tolerated than Talabostat Syngeneic Model: CT26 – mFAP+ mouse colon carcinoma – FAPα gene knock-in
Slide 21: Thank-you
© Avacta LIFE SCIENCES Thank-you Slide | 21