Antibody-based redirection of universal Fabrack-CAR T cells selectively kill antigen bearing tumor cells

Kuo, Yi-Chiu; Kuo, Cheng-Fu; Jenkins, Kurt J.; Hung, Alfur Fu-Hsin; Chang, Wen-Chung; Park, Miso; Aguilar, Brenda; Starr, Renate; Hibbard, Jonathan; Brown, Christine E.; Williams, John C.

doi:10.1136/jitc-2021-003752

Cited by 6 publications

(3 citation statements)

References 39 publications

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“…Previously, we demonstrated that this meditope-binding site is absent in human mAbs but can be readily grafted onto them; we termed the constructs meditope-enabled Abs (memAbs). We have demonstrated that the presence of the meditope does not affect antigen binding of memAbs (35)(36)(37)(38). Here, we used the technology, in concert with qSMLM, to determine how the clustering of HER2 was affected by the valency.…”

Section: Clustering Of Her2 Increases Upon Treatment With Multivalent...mentioning

confidence: 99%

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Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands

Wakefield¹,

Golfetto²,

Jorand³

et al. 2023

Front. Med.

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IntroductionThe progression-free survival of patients with HER2-positive metastatic breast cancer is significantly extended by a combination of two monoclonal antibodies, trastuzumab and pertuzumab, which target independent epitopes of the extracellular domain of HER2. The improved efficacy of the combination over individual antibody therapies targeting HER2 is still being investigated, and several molecular mechanisms may be in play: the combination downregulates HER2, improves antibody-dependent cell mediated cytotoxicity, and/or affects the organization of surface-expressed antigens, which may attenuate downstream signaling.MethodsBy combining protein engineering and quantitative single molecule localization microscopy (qSMLM), here we both assessed and optimized clustering of HER2 in cultured breast cancer cells.ResultsWe detected marked changes to the cellular membrane organization of HER2 when cells were treated with therapeutic antibodies. When we compared untreated samples to four treatment scenarios, we observed the following HER2 membrane features: (1) the monovalent Fab domain of trastuzumab did not significantly affect HER2 clustering; (2) individual therapy with either trastuzumab or (3) pertuzumab produced significantly higher levels of HER2 clustering; (4) a combination of trastuzumab plus pertuzumab produced the highest level of HER2 clustering. To further enhance this last effect, we created multivalent ligands using meditope technology. Treatment with a tetravalent meditope ligand combined with meditope-enabled trastuzumab resulted in pronounced HER2 clustering. Moreover, compared to pertuzumab plus trastuzumab, at early time points this meditope-based combination was more effective at inhibiting epidermal growth factor (EGF) dependent activation of several downstream protein kinases.DiscussionCollectively, mAbs and multivalent ligands can efficiently alter the organization and activation of the HER2 receptors. We expect this approach could be used in the future to develop new therapeutics.

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Section: Clustering Of Her2 Increases Upon Treatment With Multivalent...mentioning

confidence: 99%

“…This site has also been engineered into other mAbs which we have named meditopeenabled mAbs (memAbs) (34). MemAbs retain their affinity, selectivity, and function (35)(36)(37)(38). Importantly, this technology allows us to add unique functionality to mAbs, including "noncovalent crosslinking" through multivalent meditopes.…”

Section: Introductionmentioning

confidence: 99%

Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands

Wakefield¹,

Golfetto²,

Jorand³

et al. 2023

Front. Med.

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“…In addition, the safety‐switch mechanism TM123 redirected uni‐CAR‐T and allowed to obtain reversible toxicity in a mouse model. Proposed by Kuo et al 65 universal Fabrack‐CAR‐T, using the meditope technology, contained the meditope peptide as a tumor targeting domain, making them effective in a broad range of tumors, including CD33 expressing. A further challenge with uni‐CAR‐T is their poorer survival rate, which can be addressed by reducing their immunogenicity 66 .…”

Section: The Potential Of Personalized Allo‐car‐tmentioning

confidence: 99%

Are we ready for personalizedCAR‐Ttherapy?

Strzelec

Helbig

2023

European J of Haematology

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The future of chimeric antigen receptor T (CAR‐T) therapy remains unclear. New studies are constantly being published confirming the efficacy and favorable safety profile of its innovative enhancements. Currently approved CAR‐T drugs are manufactured exclusively for a specific patient from the recipient's own cells. This does not close the door to further modifications with subsequent personalization and better adaptation to the individual needs. Bringing such a drug to market would involve raising the already high costs, so it is necessary to lower the existing ones. On the other hand, so‐called universal CAR‐T are also getting closer to the patient's bed, but its implementation may struggle with multiple challenges, including development of graft‐versus‐host disease (GvHD) and alloimmunity. However, that off‐the‐shelf therapy could prove useful as a quick solution for patients in very poor condition or excluded from current therapy due to manufacturing limitations. The introduction of currently tested solutions may undoubtedly change the current paradigm of treatment.

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Beyond CAR-T: The rise of CAR-NK cell therapy in asthma immunotherapy

Mohammad Taheri,

Javan,

Poudineh

et al. 2024

J Transl Med

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Asthma poses a major public health burden. While existing asthma drugs manage symptoms for many, some patients remain resistant. The lack of a cure, especially for severe asthma, compels exploration of novel therapies. Cancer immunotherapy successes with CAR-T cells suggest its potential for asthma treatment. Researchers are exploring various approaches for allergic diseases including membrane-bound IgE, IL-5, PD-L2, and CTLA-4 for asthma, and Dectin-1 for fungal asthma. NK cells offer several advantages over T cells for CAR-based immunotherapy. They offer key benefits: (1) HLA compatibility, meaning they can be used in a wider range of patients without the need for matching tissue types. (2) Minimal side effects (CRS and GVHD) due to their limited persistence and cytokine profile. (3) Scalability for “off-the-shelf” production from various sources. Several strategies have been introduced that highlight the superiority and challenges of CAR-NK cell therapy for asthma treatment including IL-10, IFN-γ, ADCC, perforin-granzyme, FASL, KIR, NCRs (NKP46), DAP, DNAM-1, TGF-β, TNF-α, CCL, NKG2A, TF, and EGFR. Furthermore, we advocate for incorporating AI for CAR design optimization and CRISPR-Cas9 gene editing technology for precise gene manipulation to generate highly effective CAR constructs. This review will delve into the evolution and production of CAR designs, explore pre-clinical and clinical studies of CAR-based therapies in asthma, analyze strategies to optimize CAR-NK cell function, conduct a comparative analysis of CAR-T and CAR-NK cell therapy with their respective challenges, and finally present established novel CAR designs with promising potential for asthma treatment.

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Antibody-based redirection of universal Fabrack-CAR T cells selectively kill antigen bearing tumor cells

Cited by 6 publications

References 39 publications

Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands

Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands

Are we ready for personalizedCAR‐Ttherapy?

Beyond CAR-T: The rise of CAR-NK cell therapy in asthma immunotherapy

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