Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection

Zhukovsky, Eugene A.; Morse, R. J.; Maus, Marcela V.

doi:10.1016/j.coi.2016.02.006

Cited by 73 publications

(62 citation statements)

References 111 publications

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“…32 Alternatively, duokines can be combined with vaccination strategies or approaches of adoptive immune therapy, such as CAR-T cells or bispecific T cell-engaging molecules. 33 Duokines are not restricted to cancer therapy but might also be beneficially applied in other indications, such as viral infections, especially those being latent or chronic in nature. 34,35 Because of their modular structure, the duokine strategy described here allows combining different members of the co-stimulatory TNFSF family and thus, enables to specifically tailor the immunological responses to the therapeutic requirements.…”

Section: Discussionmentioning

confidence: 99%

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

et al. 2018

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Co-stimulatory signals induced by ligands of the tumor necrosis factor superfamily (TNFSF) play a central role in T cell activation and have emerged as a promising strategy in cancer immunotherapy. Here, we established a novel class of bifunctional co-stimulatory fusion proteins with the aim to boost T cell activation at the level of T cell – antigen-presenting cell (APC) interaction. These novel dual-acting cytokine fusion proteins were created by connecting two different homotrimeric TNFSF ligands to form homotrimeric bifunctional molecules (Duokines) or by connecting single-chain derivatives of two different homotrimeric TNFSF with a single, flexible linker (single-chain Duokines, scDuokines). By linking the TNFSF ligands 4-1BBL, OX40L and CD27L in all possible combinations, cis-acting Duokines were generated that act on the same or adjacent T cells, while combining CD40L with 4-1BBL, OX40L and CD27L resulted in trans-acting Duokines acting simultaneously on APCs and T cells. In vitro, co-stimulation of T cells was seen for cis- and trans-acting Duokines and scDuokines in an antigen-independent as well as antigen-specific setting. Trans-acting molecules furthermore activated B cells, which represent a subclass of APCs. In a pilot experiment using the syngeneic B16-FAP mouse tumor model scDuokines displayed antitumoral activity in vivo in combination with a primary T cell-activating bispecific antibody, evident from reduced number of lung metastasis compared to the antibody-only treated group. Our data show that the bifunctional, co-stimulatory duokines are capable to enhance T cell-mediated anti-tumor immune responses, suggesting that they can serve as a new class of immuno-stimulatory molecules for use in cancer immunotherapy strategies.

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Section: Discussionmentioning

confidence: 99%

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

et al. 2018

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“…53 It is thought that memory CD4 þ and especially CD8 þ lymphocytes dominate the immune response of T-cell redirecting bsAbs as these cells do not require the costimulatory signals that naïve T cells need for activation. 57 Future therapeutics may benefit from optimization of the geometry of the elicited cytolytic synapse, as well as the addition of costimulatory agonists or checkpoint inhibitors for generation of a more robust Tcell response. 57 While traditional monoclonal antibodies are restricted to the circulatory and lymphatic systems, bsAbs can facilitate delivery into otherwise unreachable compartments.…”

Section: Advantages Of Multispecificitymentioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

182

154

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Keywords: antibody(s) antibody drug(s) antibody drug conjugate(s) (ADC) physicochemical properties pharmacokinetics monoclonal antibody(s) immunotherapy IgG antibody(s) drug design developability a b s t r a c t Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.

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“…This approach has proven successful, and blinatumomab, a bispecific T-cell-engaging antibody that binds CD19 on B cells and CD3 on T cells, was approved in 2014 for the treatment of relapsed/refractory B cell precursor acute lymphoblastic leukemia [41]. Several T cell redirecting therapies are currently in clinical development against solid tumors [42]. While CD3-targeting bispecific antibodies effectively kill tumor cells, they depend on polyclonal T cells for tumor killing, and they do not directly promote activation of T cells that specifically recognize tumor-associated antigens.…”

Section: Tumor-directed Immunotherapy Can Be Achieved By Designing Drmentioning

confidence: 99%

Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation

Ellmark

Mangsbo

Furebring

et al. 2016

Cancer Immunol Immunother

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The most important goals for the field of immuno-oncology are to improve the response rate and increase the number of tumor indications that respond to immunotherapy, without increasing adverse side effects. One approach to achieve these goals is to use tumor-directed immunotherapy, i.e., to focus the immune activation to the most relevant part of the immune system. This may improve anti-tumor efficacy as well as reduce immune-related adverse events. Tumor-directed immune activation can be achieved by local injections of immune modulators in the tumor area or by directing the immune modulator to the tumor using bispecific antibodies. In this review, we focus on therapies targeting checkpoint inhibitors and co-stimulatory receptors that can generate tumor-specific T cell responses through localized immune activation.

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Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection

Cited by 73 publications

References 111 publications

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

Considerations for the Design of Antibody-Based Therapeutics

Tumor-directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation

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