Slide 1: Oncolytic Adenovirus With Hyaluronidase Activity That Evades Neutralizing Antibodies And Allows Re-administration: VCN-11
Oncolytic Adenovirus With Hyaluronidase Activity That Evades Neutralizing Antibodies And Allows Re - administration: VCN - 11 Ana Mato - Berciano , Maria V. Maliandi , Sara Morgado , Marti Farrera - Sal, Paz Moreno, Rafael Moreno, Luis A. Rojas, Gabriel Capellà , Miriam Bazan - Peregrino , Manel Cas
Slide 2: Disclosures
Disclosures R. Alemany is advisor and owns stock of VCN Biosciences / Synthetic Biologics
Slide 3: VCN-01 and VCN-11 oncolytic adenoviruses
VCN - 01 and VCN - 11 oncolytic adenoviruses Fiber Shaft RGDK Hexon ABD VCN - 01 VCN - 11 Ad5 wild type | Reduces liver tropism Fiber Shaft KKTK Host albumin | Enables replication in normal cells | Facilitates liver sequestration | Replication restricted to tumor cells (Rb - E2F defective) Degrades
Slide 4: Infection causes hyaluronan degradation
In vivo: VCN - 11 Infection causes hyaluronan degradation Melanoma SKmel28 tumors IT administration VCN - 11 expresses hyaluronidase In vitro:
Slide 5: VCN-11 binds albumin
VCN-11 binds albumin ELISA binding of ABD virus to HSA
Slide 6: VCN-01 vs VCN-11 single IV: reduced hepatic toxicity
Virus in liver at 48 h post admin. IV P B S V C N - 0 1 ( 1 X ) V C N - 1 1 ( 1 X ) 0 200 400 600 800 1000 1500 2000 2500 3000 VCN-01 vs VCN-11 single IV A L T ( I U / L ) *** P B S V C N - 1 1 ( 1 X ) V C N - 1 1 ( 3 X ) V C N - 1 1 ( 6 X ) 0 200 400 600 800 1000 1500 2000 2500 3000 VCN-11 single I
Slide 7: Reduced toxicity allows dose fractionation
Reduced VCN - 11 toxicity allows dose fractionation Increased t 1/2 for the second VCN - 11 dose (mouse model) 3 X S i n g l e 3 X ( 1 X @ 0 h + 2 X @ 4 h ) 3 X ( D 1 , D 2 , D 3 ) 0 10 20 30 40 t 1 / 2 ( m i n ) * * Dose fractionation slightly increases hepatic toxicity 5min 16min 14min 3X Dose = 1
Slide 8: Dose fractionation increases bioavailability and improves tumor targeting
Dose fractionation increases VCN - 11 bioavailability and improves tumor targeting Fiber mRNA in tumor (accumulated dose) PH20 mRNA in tumor (availability of the post - dose) • Pre - dose with an oncolytic virus (ICOVIR15KABD) not expressing PH20 @ 1X = 4E+10vp/animal to block liver kupffer cells •
Slide 9: Single administration in Naïve models
Single administration in Naïve models 20 40 80 160 320 640 1280 2560 5120 Hamster N A b T i t e r ( 1 / S e r u m D i l u t i o n ) Ad5 VCN-11 Vaccination PBS Ad5 Ad5 + Ad5 VCN-11 Ad5 + VCN-11 Ad5 VCN-11 20 40 80 160 320 640 1280 2560 5120 Mouse N A b T i t e r ( 1 / S e r u m D i l u t i o n ) * p=
Slide 10: Albumin shields against anti-Ad5 NAbs (in vitro hexon flow cytometry)
Albumin shields VCN - 11 against anti - Ad5 NAbs (in vitro hexon flow cytometry ) VCN - 01 VCN - 11 VCN - 01 VCN - 11 No neutralizing antibody + anti - Ad5 neutralizing antibody No virus Count Count FITC - A FITC - A FITC - A FITC - A FITC - A Hexon + 6% Hexon + 22% Hexon + 83% Hexon + 7% Hexon + 0.
Slide 11: Albumin shields against anti-Ad5 NAbs in vivo
Tumor cells injection Immunization Ad5 (IP) Immunization (IV) Ad5 (IV) Day 1 Day 8 Day 15 Serum collection C57BL/6 mice immunocompetent Athymic nuce mice immunodeficient Passive immunization Second admin (IV) VCN - 01 or VCN - 11 Day - 1 Day 0 0.0001 0.001 0.01 0.1 1 10 F o l d C h a n g e V G w i t
Slide 12: SK-MEL-28 shows antitumor activity in the presence of anti-Ad5 NAbs
0 10 20 30 40 50 60 70 80 90 0 250 500 750 1000 1250 1500 1750 Days T u m o u r g r o w t h ( % ) PBS VCN-01 * p<0.05 vs PBS VCN-11 * * * * SK-MEL-28 VCN - 11 shows antitumor activity in the presence of anti - Ad5 NAbs
Slide 13: Sustained tumor targeting despite high NAbs upon multiple i.v. doses
10 0 10 1 10 2 10 3 10 4 10 5 V i r a l g e n o m e s / µ g D N A ( H P - 1 T u m o u r s ) PBS VCN-11 VCN-11 + VCN-11 Vaccination ns VCN-11 # VCN-11 administrations 1 2 3 VCN-11 tumour targeting 10 20 40 80 160 320 640 1280 2560 5120 N A b T i t e r ( 1 / S e r u m D i l u t i o n ) anti-VCN-11 NAb
Slide 14: Antitumor activity in the presence of anti-Ad5 NAbs
VCN - 11 antitumor activity in the presence of antiAd5+antiVCN - 11 NAbs Non - immunized animals 0 5 10 15 20 25 30 0 200 400 600 800 1000 Pre-immunized animals PBS VCN-01 (NAbs 1/320) VCN-11 (NAbs 1/320) Days T u m o u r v o l u m e ( m m 3 ) *p<0.05 vs PBS *
Slide 15: Antitumor activity in the presence of anti-Ad5 + anti-VCN-11 NAbs
0 5 10 15 20 25 30 35 40 0 250 500 750 1000 1250 1500 Days % T u m o u r g r o w t h VCN-11 Nabs 1/320 VCN-11 Nabs 1/640 Ad5 Nabs 1/640 SW480 Tumours Naive Ad5 Nabs 1/640 + VCN-11 + PBS Passive immunity Treatment ^ * * * * * ^ * * * ^ * * * * * * * , p<0.05 vs PBS VCN - 11 antitumor activity in the
Slide 16: Conclusions
• VCN - 11 expresses functional hyaluronidase . • Reduced hepatic toxicity of the ABD - modified virus allows to “fractionate” VCN - 11 administration which improves circulating half - life and tumor targeting . • VCN - 11 administration results in lower levels of neutralizing antibodies . • VCN - 1
Slide 17: Funding and acknowledgements
This project has been funded by VCN Biosciences, a wholly owned subsidiary of Synthetic Biologics: Ana Mato Maria V. Maliandi Sheila Connelly Michael Kaleko Frank Tufaro Manel Cascalló Miriam Bazan - Peregrino Sara Morgado Martí Farrera - Sal Rafael Moreno Paz Moreno Luís Rojas Gabriel Capellà PID20