Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1

Qi, Junpeng; Li, Xiuling; Peng, Haiyong; Cook, Erika M.; Dadashian, Eman L.; Wiestner, Adrian; Park, HaJeung; Rader, Christoph

doi:10.1073/pnas.1719905115

Cited by 69 publications

(42 citation statements)

References 60 publications

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“…It was demonstrated that targeting a membrane proximal epitope also causes exclusion of the negative regulatory protein CD45 in the synapse, increasing the potency of the T-cell response and killing [15]. This observation that membrane proximal epitopes on the target antigen should provide the greatest TRBA potency has been supported with TRBA-based studies on the cancer targets P-cadherin [225] and ROR1 [226]. Second, the size of the antigen, which can effectively increase the distance within the synapse between the T-cell and target cell, also can affect potency, with much larger targets resulting in lower TRBA potencies [15,221].…”

Section: T-cell Redirecting Bispecific Antibodies (Trbas)mentioning

confidence: 98%

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

2019

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The concepts for T-cell redirecting bispecific antibodies (TRBAs) and chimeric antigen receptor (CAR)-T cells are both at least 30 years old but both platforms are just now coming into age. Two TRBAs and two CAR-T cell products have been approved by major regulatory agencies within the last ten years for the treatment of hematological cancers and an additional 53 TRBAs and 246 CAR cell constructs are in clinical trials today. Two major groups of TRBAs include small, short-half-life bispecific antibodies that include bispecific T-cell engagers (BiTE®s) which require continuous dosing and larger, mostly IgG-like bispecific antibodies with extended pharmacokinetics that can be dosed infrequently. Most CAR-T cells today are autologous, although significant strides are being made to develop off-the-shelf, allogeneic CAR-based products. CAR-Ts form a cytolytic synapse with target cells that is very different from the classical immune synapse both physically and mechanistically, whereas the TRBA-induced synapse is similar to the classic immune synapse. Both TRBAs and CAR-T cells are highly efficacious in clinical trials but both also present safety concerns, particularly with cytokine release syndrome and neurotoxicity. New formats and dosing paradigms for TRBAs and CAR-T cells are being developed in efforts to maximize efficacy and minimize toxicity, as well as to optimize use with both solid and hematologic tumors, both of which present significant challenges such as target heterogeneity and the immunosuppressive tumor microenvironment.

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Section: T-cell Redirecting Bispecific Antibodies (Trbas)mentioning

confidence: 98%

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

2019

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“…A potent immunotherapeutic approach was used to develop bispecific antibodies (biAbs) that combine a T cell-engaging arm with a tumor cell-binding arm, for which ROR1 seemed a perfect candidate due to its relatively restricted expression on tumor cells. A ROR1-targeting scFv with a membrane-proximal epitope, R11, which binds to the Kringle domain of ROR1, showed promising in vivo and ex vivo cytotoxicity against ROR1-positive cancer cells [76].…”

Section: Progress In Ror1-targeted Therapiesmentioning

confidence: 99%

Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways

Karvonen

Barker

Kaleva

et al. 2019

Cells

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Signaling via the Wnt-related receptor tyrosine kinase-like orphan receptor 1 (ROR1) triggers tumorigenic features associated with cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT), while aberrant expression of ROR1 is strongly linked to advanced disease progression and chemoresistance. Several recent studies have shown that Wnt5a binding to ROR1 promotes oncogenic signaling by activating multiple pathways such as RhoA/Rac1 GTPases and PI3K/AKT, which in turn could induce transcriptional coactivator YAP/TAZ or polycomb complex protein BMI-1 signaling, respectively, to sustain stemness, metastasis and ultimately drug-resistance. These data point towards a new feedback loop during cancer development, linking Wnt5a-ROR1 signaling activation to YAP/TAZ or BMI-1 upregulation that could play an important role in disease progression and treatment resistance. This review focuses on the crosstalk between Wnt5a-ROR1 and YAP/TAZ or the BMI-1 signaling network, together with the current advancements in targeted strategies for ROR1-positive cancers.

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“…A significant amount of research and preclinical development is being conducted on developing monoclonal antibodies to target surface ROR1 in CLL and other malignancies 11,42,43 . Also, a considerable body of work has helped us to understand signaling on the extracellular side of ROR1 via Wnt5a in CLL cells 39,44 .…”

Section: Discussionmentioning

confidence: 99%

Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1

Dave

Vondalova-Blanarova

Čada

et al. 2020

Preprint

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word count: 168 words 26 Main text word count: 4183 words 27 Number of Figures: 6 28 Number of tables: 2 29 Running title: Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1.30 Abstract 33 Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are malignancies 34 characterized by the dependence on B-cell receptor (BCR) signaling and by the high 35 expression of the cell surface receptor ROR1. Both, BCR and ROR1 are therapeutic targets 36 in these diseases and the understanding of their mutual cross talk is thus of direct 37 therapeutic relevance. In this study we analyzed the role of Lyn, a kinase from the Src 38 family, as a mediator of the BCR-ROR1 crosstalk. We confirm the functional interaction 39 between Lyn and ROR1 and demonstrate that Lyn kinase efficiently phosphorylates ROR1 40 in its kinase domain and aids the recruitment of an E3 ligase c-CBL. The absence of Lyn in 41 Lyn KO Maver-1 cells produced by CRISPR-Cas9 resulted in the increased ROR1 cell 42 surface levels and deregulated migratory properties. Similar correlations between ROR1 43 surface dynamics, levels of active Lyn and chemotactic properties were confirmed in primary 44 CLL samples. Our data establish Lyn-mediated phosphorylation of ROR1 as a point of 45 crosstalk between BCR and ROR1 signaling pathways. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 3 Introduction 60The ROR protein family comprises of ROR1 and ROR2, which are both type 1 61 transmembrane receptors. Upon discovery, ROR proteins were referred to as orphan 62 receptors on account of the lack of identity of their ligands. However, subsequent studies 63 identified their ligands to be the Wnt proteins, mostly Wnt-5a protein 1,2 . Wnt-5a/ROR 64 pathway is an essential signaling pathway that controls cell polarity and migration during 65 embryonic development and tissue homeostasis 3,4 . During embryonic development, RORs 66 are highly and uniformly expressed, most prominently in the skeletal and neural tissues, but 67 postnatally their expression becomes highly restricted 5 . 68Interestingly, ROR1 or ROR2 upregulation has been observed in many cancers: 69ROR1 is upregulated in solid tumors or hematologic malignancies while ROR2 is 70 overexpressed in osteosarcomas or renal cell carcinomas 6 . High expression of ROR1 is 71 typical for some B-cell lymphomas such as mantle cell lymphoma (MCL) 7 and chronic 72 lymphocytic leukemia(CLL) 8,9 . CLL is a form of hematologic cancer which is manifested as a 73 steady accumulation of mature CD5 + B-cells in the bone marrow, lymphoid tissues and 74 peripheral blood. It is the most common form of adult leukemia in the western hemisphere, 75with an incidence of 5 per 100 000 each year and an average median age of on-set around 76 70 years. Most of the CLL cases remain asymptomatic for a long time, in which case 77 therapeutic intervention is not necessary. However, part of the CLL cases progress rapidly, 78 require treatment and their overall life expectancy is decreased 10 . 79CLL cells are in most cases hig...

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Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1

Cited by 69 publications

References 60 publications

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells

Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways

Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1

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