Novel anti-CD30/CD3 bispecific antibodies activate human T cells and mediate potent anti-tumor activity. Front Immunol 2023;14:1225610
Date
08/30/2023Pubmed ID
37646042Pubmed Central ID
PMC10461807DOI
10.3389/fimmu.2023.1225610Scopus ID
2-s2.0-85168950041 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
CD30 is expressed on Hodgkin lymphomas (HL), many non-Hodgkin lymphomas (NHLs), and non-lymphoid malignancies in children and adults. Tumor expression, combined with restricted expression in healthy tissues, identifies CD30 as a promising immunotherapy target. An anti-CD30 antibody-drug conjugate (ADC) has been approved by the FDA for HL. While anti-CD30 ADCs and chimeric antigen receptors (CARs) have shown promise, their shortcomings and toxicities suggest that alternative treatments are needed. We developed novel anti-CD30 x anti-CD3 bispecific antibodies (biAbs) to coat activated patient T cells (ATCs) ex vivo prior to autologous re-infusions. Our goal is to harness the dual specificity of the biAb, the power of cellular therapy, and the safety of non-genetically modified autologous T cell infusions. We present a comprehensive characterization of the CD30 binding and tumor cell killing properties of these biAbs. Five unique murine monoclonal antibodies (mAbs) were generated against the extracellular domain of human CD30. Resultant anti-CD30 mAbs were purified and screened for binding specificity, affinity, and epitope recognition. Two lead mAb candidates with unique sequences and CD30 binding clusters that differ from the ADC in clinical use were identified. These mAbs were chemically conjugated with OKT3 (an anti-CD3 mAb). ATCs were armed and evaluated in vitro for binding, cytokine production, and cytotoxicity against tumor lines and then in vivo for tumor cell killing. Our lead mAb was subcloned to make a Master Cell Bank (MCB) and screened for binding against a library of human cell surface proteins. Only huCD30 was bound. These studies support a clinical trial in development employing ex vivo-loading of autologous T cells with this novel biAb.
Author List
Faber ML, Oldham RAA, Thakur A, Rademacher MJ, Kubicka E, Dlugi TA, Gifford SA, McKillop WM, Schloemer NJ, Lum LG, Medin JAAuthors
Theresa A. Dlugi PhD Research Scientist I in the Obstetrics and Gynecology department at Medical College of WisconsinJeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin
Nathan Schloemer MD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAnimals
Antibodies, Bispecific
Antibodies, Monoclonal
Ataxia Telangiectasia
Child
Ehlers-Danlos Syndrome
Hodgkin Disease
Humans
Lymphoma, Non-Hodgkin
Mice
Muromonab-CD3
