A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells

Seung, Edward; Xing, Zhen; Wu, Lan; Rao, Ercole; Cortez-Retamozo, Virna; Ospina, Beatriz; Chen, Liqing; Beil, Christian; Song, Zhili; Zhang, Bailin; Levit, Mikhail; Deng, Gejing; Hebert, Andrew; Kirby, Patrick J.; Li, Aiqun; Poulton, Emma-Jane; Vicente, Rita; Garrigou, Audrey; Piepenhagen, Peter; Ulinski, Greg; Sanicola-Nadel, Michele; Bangari, Dinesh S.; Qiu, Huawei; Pao, Lily; Wiederschain, Dmitri; Wei, Ronnie R.; Yang, Zhiyong; Nabel, Gary J.

doi:10.1038/s41586-022-04439-0

Cited by 75 publications

(40 citation statements)

References 39 publications

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“…A recent study has found that engineered CAR-T cells coupled with a CD2 receptor may overcome resistance due to CD58 loss in an in vivo model of DLBCL 20 . In solid tumors, trispecific antibodies were recently shown to be effective in targeting CD28+ T cells against HER2+ breast cancer in vivo 38 ; similar antibodies might be engineered to instead stimulate T cells via CD2 in a targeted manner. The utility of CD2 co-stimulation could be expanded to CD28+CD8+ T cell populations as well, as recent work demonstrates that CD2 and CD28 co-stimulation are comparable in their ability to promote proliferation, cytokine production, and effector differentiation in naïve T cells, though CD2 stimulation more efficiently maintains a pool of progenitor-like T cells that are important for response to PD-1 blockade 39 .…”

Section: Discussionmentioning

confidence: 99%

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

Melms

Rogava

et al. 2022

Preprint

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The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 co-immunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary co-stimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.

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Section: Discussionmentioning

confidence: 99%

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

Melms

Rogava

et al. 2022

Preprint

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“…6 ). In this case, DBMN played a bridging role in connecting T cell and tumor cell, which was adopted in the latest studies seem to strengthen the inhibitory ability of T cells [ 28 , 29 ], demonstrating a superior tumor-specific accumulation and effector killing.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…Unfortunately, we found although the number of T cells (modified with conventional magnetic nanoparticles) could significantly increase in the experiments, it fell sharply as soon as the magnetic field removed, which meant patients need keep stiff in an intense magnetic field or an MRI machine for a long time and poor treatment efficiency. Thus, a linker between cytotoxic T lymphocyte (CTL) and tumor cell might enhance the residence time and killing ability of T cells [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Dual-binding nanoparticles improve the killing effect of T cells on solid tumor

Luo

et al. 2022

J Nanobiotechnol

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Adoptive cell therapy (ACT) was one of the most promising anti-tumor modalities that has been confirmed to be especially effective in treating hematological malignancies. However, the clinical efficacy of ACT on solid tumor was greatly hindered by the insufficient tumor-infiltration of cytotoxic CD8 + T cells. Herein, we constructed a nanoplatform termed dual-binding magnetic nanoparticles (DBMN) that comprised PEG-maleimide (Mal), hyaluronic acid (HA) and Fe3O4 for adoptive T cell-modification and ACT-sensitization. After a simple co-incubation, DBMN was anchored onto the cell membrane (Primary linking) via Michael addition reaction between the Mal and the sulfhydryl groups on the surface of T cells, generating magnetized T cells (DBMN-T). Directed by external magnetic field and in-structure Fe3O4, DBMN-T was recruited to solid tumor where HA bond with the highly expressed CD44 on tumor cells (Secondary Linking), facilitating the recognition and effector-killing of tumor cells. Bridging adoptive T cells with host tumor cells, our DBMN effectively boosted the anti-solid tumor efficacy of ACT in a mouse model and simultaneously reduced toxic side effects.

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“…Multi-specific biological molecules, especially bispecific antibodies and their derivatives scFvs, have rapidly grown clinic attention due to the unique advantages of providing off-the-shelf immunotherapeutics for treating cancer [36][37][38]. However, as with any immunotherapy, safety and offtarget toxicity issues are a potential concern.…”

Section: Discussionmentioning

confidence: 99%

Ultra-small bispecific fusion protein augments tumor penetration and treatment efficacy for pancreatic cancer

Wang

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Due to drugs' low intrinsic anticancer activity and the unique physiological barrier of PDAC tumors, the once highly anticipated antibody-based pathway-targeted therapies have not achieved promising improvement in outcomes. Here, an ultra-small-sized bispecific fusion protein, termed Bi-fp50, that could largely enrich deep tumor tissue and effectively inhibit PDAC tumor growth was reported. The bispecific Bi-fp50 protein was constructed by a typical synthetic biology method that could efficiently target EGFR and VEGF of PDAC cells simultaneously in vitro and in vivo. For Bxpc3 and Aspc1 PDAC cells, the Bi-fp50 achieved a significant and synergistic therapeutic effect. Owing to the small size of only 50 kDa and the function of reducing the interstitial fluid pressure by vascular normalization, the Bi-fp50 showed enhanced penetration, considerable accumulation, and uniform distribution in tumor and subsequently led to effective inhibition of the growth of Bxpc3 cells-induced PDAC tumor in vivo. Furthermore, no noticeable side effect of Bi-fp50 was found in vitro and in vivo. This work demonstrates that the synthetic Bi-fp50 fusion protein could be used as a new effective pathway-specific targeted therapy for PDACs.

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A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells

Cited by 75 publications

References 39 publications

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

Dual-binding nanoparticles improve the killing effect of T cells on solid tumor

Ultra-small bispecific fusion protein augments tumor penetration and treatment efficacy for pancreatic cancer

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