Convection-Enhanced Delivery of a First-in-Class Anti-β1 Integrin Antibody for the Treatment of High-Grade Glioma Utilizing Real-Time Imaging

Abstract

Introduction: OS2966 is a first-in-class, humanized and de-immunized monoclonal antibody which targets the adhesion receptor subunit, CD29/β1 integrin. CD29 expression is highly upregulated in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy. Here, we present a novel Phase I clinical trial design addressing several factors plaguing effective treatment of high-grade gliomas (HGG). Study Design: This 2-part, ascending-dose, Phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically indicated resection. In Study Part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which will be used for the intratumoral, convection-enhanced delivery (CED) of OS2966. Gadolinium contrast will be added to OS2966 before each infusion, enabling the real-time visualization of therapeutic distribution via MRI. Subsequently, patients will undergo their clinically indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design. Discussion: The present study design leverages multiple innovations including: (1) the latest CED technology, (2) 2-part design including neoadjuvant intratumoral administration, (3) a first-in-class investigational therapeutic, and (4) concentration-based dosing. Trial registration: A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

“…Direct delivery into the CNS: Direct antibody delivery into the brain and therapeutic effects were successfully achieved after intracerebroventricular injection ( Cheng et al, 2017 ; Du et al, 2020 ; Gros-Louis, Soucy, Lariviere, & Julien, 2010 ; Klyubin et al, 2005 ; Qiang et al, 2018 ; Thakker et al, 2009 ; Yadav et al, 2017 ), intracerebral injection ( Brendza et al, 2005 ; Grossi et al, 2003 ; Lombardo et al, 2003 ; Wilcock et al, 2003 ) and convection-enhanced delivery ( Nwagwu, Immidisetti, Bukanowska, Vogelbaum, & Carbonell, 2020 ; Shoji et al, 2016 ; Souweidane et al, 2018 ). Although potentially effective, such neurosurgical methods are technically challenging, highly invasive, and raise serious safety concerns ( Cohen-Pfeffer et al, 2017 ; Pardridge, 2007 ).…”

“…A new technique, which uses brain-focused ultrasound (FUS) ( Costa, Joaquim, Forlenza, Talib, & Gattaz, 2019 ) to sonicate systematically administered microbubbles, can reversibly and locally disrupt tight junctions ( Shang, Wang, Liu, Zhang, & Xue, 2011 ; Sheikov, McDannold, Sharma, & Hynynen, 2008 ) and increase active transcytosis in the BBB ( Sheikov et al, 2006 ), allowing antibody transport from the blood to specific brain regions. This method was found to be safe in non-human primates ( McDannold, Arvanitis, Vykhodtseva, & Livingstone, 2012 ; Nwagwu et al, 2020 ), and recently in humans ( Abrahao et al, 2019 ; Carpentier et al, 2016 ). In addition, brain-focused ultrasound was found to downregulate the efflux transporter, P-glycoprotein, in the targeted brain regions (H. Cho et al, 2016 ).…”

Novel Strategies for Nanoparticle-Based Radiosensitization in Glioblastoma

“…In this regard, CED of OS2966, an anti-CD29 (Beta1 integrin) monoclonal antibody, was included in a phase 1 study to determine if this drug, when delivered directly to the brain of adult patients with recurrent/progressive high-grade glioma (HGG), is safe and well tolerated [ 63 ]. This study is an open-label, dose-escalation, two-part study.…”

Involvement of integrin-activating peptides derived from tenascin-C in colon cancer progression

“…[ 123 ]). Regarding other therapeutic modalities, OS2966, a humanized monoclonal antibody targeting human beta1-integrins, is undergoing testing in a phase I clinical trial for the treatment of recurrent/progressive glioma[ 124 ]. In addition, one possible strategy may be to develop drugs with modes of inhibition other than competitive inhibition of integrin.…”