Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Slaga, Dionysos; Ellerman, Diego; Lombana, T. Noelle; Vij, Rajesh; Li, Ji; Hristopoulos, Maria; Clark, Robyn; Johnston, Jennifer; Shelton, Amy L.; Mai, Elaine; Gadkar, Kapil; Lo, Amy A.; Koerber, James T.; Tótpál, Klára; Prell, Rodney A.; Lee, Genee; Spiess, Christoph; Junttila, Teemu T.

doi:10.1126/scitranslmed.aat5775

Cited by 103 publications

(107 citation statements)

References 54 publications

(71 reference statements)

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“…These include T-cell redirecting bispecific (TCB) formats in combination with an anti-CD3 arm, as well as the use of the 129 variable regions for reformatting for chimeric antigen receptor (CAR)-T approaches, both of which rely on minimal normal tissue cross-reactivity (46). Recently, an attractive strategy for increased tumor-specific targeting in the TCB setting was proposed in the shape of an avidity-optimized HER2 TCB (47). This strategy hinged on the combination of low monovalent target affinity, precluding normal tissue (with low target expression) binding, with avidity-driven tumor targeting and this approach could be relevant for the 129 mAb.…”

Section: Discussionmentioning

confidence: 99%

Monoclonal Antibody Targeting Sialyl-di-Lewisa–Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential

Tivadar

McIntosh

Chua

et al. 2020

Molecular Cancer Therapeutics

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Tumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal cancer therapy. FG129, obtained through BALB/c mouse immunizations with liposomes containing membrane glycan extracts from the colorectal cancer cell line LS180, is an mIgG1k that targets sialyl-di-Lewis a-containing glycoproteins. FG129, as well as its chimeric human IgG1 variant, CH129, binds with nanomolar functional affinity to a range of colorectal, pancreatic, and gastric cancer cell lines. FG129 targets 74% (135/182) of pancreatic, 50% (46/92) of gastric, 36% (100/281) of colorectal, 27% (89/327) of ovarian, and 21% (42/201) of non-small cell lung cancers, by IHC. In our pancreatic cancer cohort, high FG129 glyco-epitope expression was significantly associated with poor prognosis (P ¼ 0.004). Crucially, the glyco-epitope displays limited normal tissue distribution, with FG129 binding weakly to a small percentage of cells within gallbladder, ileum, liver, esophagus, pancreas, and thyroid tissues. Owing to glyco-epitope internalization, we validated payload delivery by CH129 through monomethyl auristatin E (MMAE) or maytansinoid (DM1 and DM4) conjugation. All three CH129 drug conjugates killed high-binding colorectal and pancreatic cancer cell lines with (sub)nanomolar potency, coinciding with significant in vivo xenograft tumor control by CH129-vcMMAE. CH129, with its restricted normal tissue distribution, avid tumor binding, and efficient payload delivery, is a promising candidate for the treatment of sialyl-di-Lewis aexpressing solid tumors, as an antibody-drug conjugate or as an alternative cancer immunotherapy modality.

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Section: Discussionmentioning

confidence: 99%

Monoclonal Antibody Targeting Sialyl-di-Lewisa–Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential

Tivadar

McIntosh

Chua

et al. 2020

Molecular Cancer Therapeutics

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“…Blinitumimab, a CD19‐directed T‐cell bispecific engager, has entered the standard of care for adult and pediatric patients with pre‐B ALL . Although no BiTEs are presently approved for solid malignancies, clinical data are beginning to emerge targeting HER2 and CEA with next‐generation variations of bispecific technology. TCR mimics are structurally identical to conventional MoAbs but have specificity for only a single antigen, in contrast with BiTEs .…”

Section: Engineering Exogenous Tcrs To Enhance Safety Function and mentioning

confidence: 99%

“…Blinitumimab, a CD19-directed Tcell bispecific engager, has entered the standard of care for adult and pediatric patients with pre-B ALL. 150,151 Although no BiTEs are presently approved for solid malignancies, clinical data are beginning to emerge targeting HER2 152…”

Section: Soluble Tcrs T-cell Engaging Bispecifics and Tcr-mimeticsmentioning

confidence: 99%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

224

185

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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“…Dr. Karen Staflin (Genentech) provided a case example of a human epidermal growth factor receptor 2 (HER2) CD3 bispecific to demonstrate the impact of binding affinity (coined affinity tuning) to CD3 and/or TAA on nonclinical efficacy and tolerability (Junttila et al 2014;Slaga et al 2018). Because HER2 is widely expressed in normal tissues, there were concerns about on-target/off-tumor cytotoxicity and cytokine release.…”

Section: Session 2: Target (Tumor Antigen) Expression and Liability Amentioning

confidence: 99%

Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics

Kamperschroer

Shenton

Lebrec

et al. 2020

Journal of Immunotoxicology

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Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized. ARTICLE HISTORY

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Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Cited by 103 publications

References 54 publications

Monoclonal Antibody Targeting Sialyl-di-Lewisa–Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential

Monoclonal Antibody Targeting Sialyl-di-Lewisa–Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics

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