Phage display generation of a novel human anti‐CD1A monoclonal antibody with potent cytolytic activity

Abstract

Summary CD1A is a cell surface protein expressed on Langerhans cells and cortical thymocytes that could potentially be used as an immunotherapeutic target in Langerhans Cell Histiocytosis (LCH), the cortical subtype of T‐cell acute lymphocytic leukaemia (T‐ALL) and other CD1A‐positive tumours. The monoclonal antibody (mAb) CR2113 was selected from a panel of six fully human mAbs isolated from a semi‐synthetic phage display library, based on specificity and avidity against cells expressing CD1 antigen variants. CR2113 recognized CD1A in T‐ALL cell lines and patient samples. Confocal microscopy revealed that the CR2113‐CD1A complex was internalized at 37°C. Furthermore, while CR2113 induced moderate complement‐dependent cytotoxicity (CDC), potent antibody‐dependent cell cytotoxicity (ADCC) activity was observed against CD1A expressing cell lines as well as T‐ALL cell lines and T‐ALL patient samples. In vivo experiments showed that CR2113 as a naked antibody has modest but specific anti‐tumour activity against CD1A‐expressing tumours. CR2113 is a high‐affinity human anti‐CD1A mAb with significant ADCC activity. These properties make CR2113 a candidate for clinical diagnostic imaging and therapeutic targeting of LCH as well as potential use in other clinical applications.

Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

“…CD1a is a lipid-presenting molecule whose expression is essentially restricted to coT-ALL and Langerhans cell (LC) histiocytosis and is practically absent in human tissues with the exception of developing cortical thymocytes and LC. 28,29 Here, we tested the feasibility of targeting CD1a 1 coT-ALL using CD1a CARTs. We report that CD1a-specific CARTs exhibit robust cytotoxicity against CD1a 1 coT-ALL cell lines and primary coT-ALL cells, both in vitro and in vivo.…”

Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions

“…CD1a is a lipid-presenting molecule whose expression is restricted to developing cortical thymocytes, skin Langerhans cells, and some circulating myeloid dendritic cells [103,104]. Neither T cells nor CD34 + hematopoietic progenitors express CD1a, making it a fratricideresistant target, while limiting the risk of on-target/offtumor toxicity.…”

New Insights Into the Molecular Pathogenesis of Langerhans Cell Histiocytosis

“…However, these innovative strategies, particularly if associated with a therapeutic vaccination with autologous tolerogenic dendritic cells, should be fine-tuned in preclinical studies before assessing their relevance to the clinical practice [89]. In contrast, a fully human anti-CD1a moAb, namely CR2113, was recently produced and provided powerful antibody-dependent cell cytotoxicity activity in vitro, whereas only a modest antitumor effect was shown in CD1a-expressing xenograft models [121]. However, the highly specific targeting capacity found in vivo can provide the basis for future development of CR2113 for diagnostic imaging and/or treatment modality, thus fostering studies aimed at improving its antitumor activity by radiolabeling and/or by conjugation with immunotoxins or BRAF inhibitors.…”