Peptide-scFv antigen recognition domains effectively confer CAR T cell multiantigen specificity
Year: 2024
Type: article
Abstract: The emergence of immune escape is a significant roadblock to developing effective chimeric antigen receptor (CAR) T cell therapies against hematological malignancies, including acute myeloid leukemia (AML). Here, we demonstrate feasibility of targeting two antigens simultaneously by combining a GRP78-specific peptide antigen recognition domain with a CD123-specific scFv to generate a peptide-scFv bispecific antigen recognition domain (78.123). To achieve this, we test linkers with varying length and flexibility and perform immunophenotypic and functional characterization. We demonstrate that bispecific CAR T cells successfully recognize and kill tumor cells that express GRP78, CD123, or both antigens and have improved antitumor activity compared to their monospecific counterparts when both antigens are expressed. Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations.
Source: Cell Reports Medicine
Authors: Jaquelyn T. Zoine, Kalyan Immadisetty, Jorge Ibanez-Vega, Sarah E. Moore, Chris Nevitt, Unmesha Thanekar, Liqing Tian, Abbas Karouni, Peter J. Chockley, Bright Arthur, Heather Sheppard, Jeffery M. Klco, Deanna M. Langfitt, Giedre Krenciute, Stephen Gottschalk, M. Madan Babu, M. Paulina Velasquez
Institution: St. Jude Children's Research Hospital
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
OpenAlex ID: W4391745166