Developing a Membrane-Proximal CD33-Targeting CAR T Cell

Authors

Ruby Freeman
Sanam Shahid
Abdul G Khan
Serena C Mathew
Sydney Souness
Erin R Burns
Jasmine S Um
Kento Tanaka
Winson Cai
Sarah Yoo
Andrew Dunbar
Young Park
Devin McAvoy
Kinga K Hosszu
Ross L Levine
Jaap Jan Boelens
Ivo C Lorenz
Renier J Brentjens
Anthony F Daniyan

Publication Date

5-20-2024

Journal

The Journal for ImmunoTherapy of Cancer

Abstract

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.

METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.

RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy.

CONCLUSIONS: Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.

Keywords

Humans, Animals, Mice, Sialic Acid Binding Ig-like Lectin 3, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, Leukemia, Myeloid, Acute, T-Lymphocytes, Xenograft Model Antitumor Assays, Cell Line, Tumor

Comments

Supplementary Materials

PMID: 38772686