Life science
Medical & heathcare, Drug discovery, Cancer therapy

Development of a novel oncolytic adenovirus that can overcome theproblems of a conventional oncolytic adenovirus
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences
Associate Professor Fuminori Sakurai

Researchmap https://researchmap.jp/read0165081

Professor Hiroyuki Mizuguchi

Researchmap https://researchmap.jp/read0165079

Neutralizing Anti-Ad55型アデノウイルスantibodyに対する抗体

Oncolytic adenoviruses (OAds) are among the most promisingoncolytic viruses. Almost all oncolytic adenoviruses are composedof human adenovirus serotype 5 (Ad5) (OAd5). However, expression of the primary infection receptor for Ad5, coxsackievirus-adenovirus receptor (CAR), often declines on malignant tumor cells. Inaddition, at least 80% of adults have neutralizing antibodies against
Ad5. In order to overcome these problems, we developed a novel
OAd fully composed of human adenovirus serotype 35 (OAd35).
OAd35 recognizes CD46, which is ubiquitously expressed on almost all human cells and is often upregulated on malignant tumorcells, as an infection receptor. Moreover, 20% or fewer adults haveneutralizing antibodies against Ad35. OAd35 mediated efficient
cell lysis activities in various types of tumor cells. Anti-Ad5 serum
did not inhibit OAd35-mediated in vitro tumor cell lysis. OAd35
significantly suppressed growth of the subcutaneous CAR-positive
and CAR-negative tumors following intratumoral administration.
These results indicated that OAd35 is a promising alternative oncolytic virus for OAd5.

腫瘍溶解性
Oncolytic
5型アデノウイルス
Ad serotype 5CARCAR（5型アデノウイルスの感染受容体）(infection receptor for

Ad serotype 5)

CD46CD46(infection receptor for Ad（35型アデノウイルスの感染受容体）
serotype 35)

CAR-CAR陰性・CD46陽性
negative and CD46-positive
Tがん細胞
umor cellsのn概Advantages of o図
nc１o．ly本
tic研a究deov略
irus serotype 35▍ Background & Results
Oncolytic viruses, which can specifically replicate in and killtumor cells without apparent toxicity to normal cells, are attracting
much attention as a novel cancer therapeutic agent. Among various types of oncolytic viruses, the oncolytic adenoviruses (OAds)
are one of the most promising. Almost all OAds are composed ofhuman adenovirus (Ad) serotype 5 (Ad5), which belongs to species C. However, the OAd composed of Ad5 (OAd5) has two majordrawbacks. OAd5 recognizes coxsackievirus-adenovirus receptor(CAR) as an infection receptor. CAR expression is often reducedon malignant tumor cells, leading to inefficient infection with OAd5.
In addition, more than 80% of adults have neutralizing antibodies
against Ad5 due to natural infection with Ad5 during childhood.
In order to overcome these drawbacks, we developed a novel
OAd fully composed of human Ad serotype 35 (Ad35) (OAd35),
which belongs to species B2. Ad35 recognizes human CD46 as
an infection receptor. CD46, which is a complement regulatory
protein, is ubiquitously expressed on all human cells except erythrocytes. Moreover, CD46 is often upregulated on malignant tumorcells. In addition, 20% or fewer adults have neutralizing antibodies
against Ad35. OAd35 efficiently killed not only CAR-positive but
also CAR-negative tumor cells. Anti-Ad5 serum did not inhibit theOAd35-mediated tumor cell killing. Intratumoral administration ofOAd35 resulted in significant growth suppression of the subcutaneous CAR-positive and CAR-negative tumors.

腫瘍溶解性Oncolytic
35型アデノウイルス
Ad serotype 35CARCAR陽性・CD46陽性- and CD46-positive
Tuがん細胞
mor cells

1,500

Tumor volume (mm3)Life science

Abstract

PBS

1,000500*0OAd serotype 35
05101520

Days after administration

Tumor volumes following intratumoral administrationof oncolytic Ad serotype 35 in tumor-bearing mice

▍ Significance of the research and Future perspective
OAd35 can become a promising alternative oncolytic virus, especially for tumors resistant to a conventional oncolytic Ad.

P a t e n t PCT/JP2020/006383
Ono, Ryosuke; Sakurai, Fuminori; Mizuguchi, Hiroyuki et al. Efficient antitumor effects of a novel oncolytic adenovirus fully composed of species B adenoTr e a t i s evirus serotype 35. Mol. Ther. Oncolytics. 2021; 20: 399-409. doi: 10.1016/j.omto.2021.01.015.
UR
L https://resou.osaka-u.ac.jp/ja/research/2021/20210217_2
K e y w o r d oncolytic virus, adenovirus, cancer, neutralizing antibody