High scFv-receptor affinity does not enhance the antitumor activity of HER2-retargeted measles virus

Area of Science:

• Oncolytic virology
• Immunotherapy
• Cancer biology

Background:

• Oncolytic viruses are engineered to selectively target and destroy cancer cells.
• Targeting the HER2/neu (HER2) receptor is a strategy for treating HER2-positive cancers.
• Measles virus (MV) is a promising platform for oncolytic virotherapy.

Purpose of the Study:

• To investigate the relationship between ligand-receptor affinity and the antitumor efficacy of HER2-targeted oncolytic measles viruses (MVs).
• To determine if higher affinity binding translates to improved oncolytic activity and therapeutic potency in vitro and in vivo.

Main Methods:

• A panel of six HER2-targeted MVs with varying single-chain antibody (scFv) affinities (10^-6 to 10^-11 M) was constructed.
• In vitro studies assessed viral infection and cytopathic effects (syncytia formation) in SKOV3ip.1 human ovarian cancer cells.
• In vivo studies evaluated the therapeutic activity of these MVs against orthotopic SKOV3ip.1 tumor xenografts in athymic mice.

Main Results:

• All MVs infected SKOV3ip.1 cells in vitro.
• Only high-affinity MVs (Kd ≥ 10^-8 M) induced significant cytopathic effects in vitro.
• All six MVs demonstrated therapeutic activity in vivo against ovarian tumor xenografts.
• MVs with higher affinity scFvs (Kd = 10^-9 to 10^-11 M) did not show significantly superior antitumor activity compared to lower-affinity MVs (Kd ≤ 10^-8 M).

Conclusions:

• Increasing the receptor affinity of the MV attachment protein has a minimal impact on in vivo therapeutic efficacy.
• In vitro cytopathic effects do not fully predict in vivo antitumor potency for these HER2-targeted MVs.
• Receptor affinity may be less critical than other factors for the in vivo efficacy of oncolytic MVs targeting HER2-expressing tumors.