Engineering of a trispecific tumor-targeted immunotherapy incorporating 4-1BB co-stimulation and PD-L1 blockade

Warmuth, Stefan; Gunde, Tea; Snell, Daniel C.; Brock, Matthias; Weinert, Christoph H.; Simonin, Alexandre; Hess, Christian; Tietz, Julia; Johansson, Maria H.; Spiga, Fabio Mario; Heiz, Robin; Flückiger, Naomi; Wagen, Sandro; Zeberer, Julia; Diem, Dania; Mahler, Dana; Wickihalder, Belinda; Muntwiler, Simone; Chatterjee, Bithi; Küttner, Benjamin; Bommer, Bettina; Yaman, Yasemin; Lichtlen, Peter; Urech, David

doi:10.1080/2162402x.2021.2004661

Cited by 18 publications

(21 citation statements)

References 61 publications

(62 reference statements)

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“…PRS-344/S095012 presents a relative affinity difference of 7, with a higher affinity to PD-L1, potentially driving the biodistribution of the drug to PD-L1–high environments like the tumor ( 68 ). Furthermore, it has been demonstrated in an assay format, that maximizes target bioavailability, that higher affinity to PD-L1 compared with 4-1BB favors the optimal stimulation of T cells in vitro ( 61 ). However, data from patients will educate whether this translates into the clinical setting, since in patients, T-cell stimulation might be further impacted by other factors such as the density, dynamic expression, and internalization events of both targets ( 58, 68 ).…”

Section: Discussionmentioning

confidence: 99%

The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner

Peper-Gabriel

Pavlidou

Pattarini

et al. 2022

Clinical Cancer Research

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Purpose: While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due to resistant or refractory tumors. A combination of checkpoint blockade with further T-cell stimulation mediated by 4-1BB agonism may increase response rates and durability of response. A bispecific molecule that blocks the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis and localizes 4-1BB costimulation to a PD-L1–positive (PD-L1+) tumor microenvironment (TME) or tumor draining lymph nodes could maximize antitumor immunity and increase the therapeutic window beyond what has been reported for anti–4-1BB mAbs. Experimental Design: We generated and characterized the PD-L1/4-1BB bispecific molecule PRS-344/S095012 for target binding and functional activity in multiple relevant in vitro assays. Transgenic mice expressing human 4-1BB were transplanted with human PD-L1–expressing murine MC38 cells to assess in vivo antitumoral activity. Results: PRS-344/S095012 bound to its targets with high affinity and efficiently blocked the PD-1/PD-L1 pathway, and PRS-344/S095012-mediated 4-1BB costimulation was strictly PD-L1 dependent. We demonstrated a synergistic effect of both pathways on T-cell stimulation with the bispecific PRS-344/S095012 being more potent than the combination of mAbs. PRS-344/S095012 augmented CD4-positive (CD4+) and CD8-positive (CD8+) T-cell effector functions and enhanced antigen-specific T-cell stimulation. Finally, PRS-344/S095012 demonstrated strong antitumoral efficacy in an anti–PD-L1–resistant mouse model in which soluble 4-1BB was detected as an early marker for 4-1BB agonist activity. Conclusions: The PD-L1/4-1BB bispecific PRS-344/S095012 efficiently combines checkpoint blockade with a tumor-localized 4-1BB–mediated stimulation burst to antigen-specific T cells, more potent than the combination of mAbs, supporting the advancement of PRS-344/S095012 toward clinical development. See related commentary by Shu et al., p. 3182

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Section: Discussionmentioning

confidence: 99%

The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner

Peper-Gabriel

Pavlidou

Pattarini

et al. 2022

Clinical Cancer Research

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“…In terms of the trispecific antibodies that are currently undergoing clinical trials (CB307, NM21-1480), like the bispecifics, they are mainly designed to target 4-1BB along with another tumor-driving or associated factor. In addition to those binding domains, they are composed of an additional, third domain that binds to human serum albumin (HSA), which serves the purpose of prolonging the serum half-life of the antibodies ( 100 ). Even more, Compte et al have developed a bispecific 4-1BB agonistic Fc-free trimerbody composed of three 4-1BB binding single-chain variable fragments (scFv) and three EGFR binding antibodies for use in cancer treatment ( 101 ).…”

Section: -1bb In Cancer Immunotherapymentioning

confidence: 99%

4-1BB: A promising target for cancer immunotherapy

2022

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Immunotherapy, powered by its relative efficacy and safety, has become a prominent therapeutic strategy utilized in the treatment of a wide range of diseases, including cancer. Within this class of therapeutics, there is a variety of drug types such as immune checkpoint blockade therapies, vaccines, and T cell transfer therapies that serve the purpose of harnessing the body’s immune system to combat disease. Of these different types, immune checkpoint blockades that target coinhibitory receptors, which dampen the body’s immune response, have been widely studied and established in clinic. In contrast, however, there remains room for the development and improvement of therapeutics that target costimulatory receptors and enhance the immune response against tumors, one of which being the 4-1BB (CD137/ILA/TNFRSF9) receptor. 4-1BB has been garnering attention as a promising therapeutic target in the setting of cancer, amongst other diseases, due to its broad expression profile and ability to stimulate various signaling pathways involved in the generation of a potent immune response. Since its discovery and demonstration of potential as a clinical target, major progress has been made in the knowledge of 4-1BB and the development of clinical therapeutics that target it. Thus, we seek to summarize and provide a comprehensive update and outlook on those advancements in the context of cancer and immunotherapy.

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“…[89,90] The efficacy, safety, and immunogenicity of NM21-1480-a trispecific antibody targeting PD-L1, 4-1BB, and human serum albumin (HSA)-have been evaluated in patients with advanced solid tumors. [91] The pharmacodynamics of NM21-1480 have also been evaluated in a phase II clinical trial (ClinicalTrials.gov Identifier: NCT04442126) in adult patients with NSCLC. A trispecific T cell-activating construct containing three humanized antibodyderived binding domains, including HPN217 targeting BCMA for tumor binding, albumin for half-life extension, and CD3 for T cell engagement, has been developed (ClinicalTrials.gov Identifier: NCT04184050).…”

Section: T Cell-or Nk Cell-engaging Trispecific Antibody Constructs F...mentioning

confidence: 99%

Emerging Antibodies in Cancer Therapy

Sun

2022

Advanced NanoBiomed Research

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Since the first monoclonal antibody, Orthoclone OKT3, was approved in 1986 for the treatment of acute allograft rejection in renal transplant recipients, the number of antibody‐based therapies has increased remarkably, with more than 130 monoclonal antibodies being currently available. In particular, due to their robust binding affinity and high specificity, various monoclonal antibodies have achieved success as complementary antitumor drugs. Moreover, therapeutic potency can be improved by engineering Y‐shaped binding sites of the antibodies to simultaneously recognize two distinct antigens; such molecules are called bispecific antibodies and function as a bridge, with one site binding to a tumor‐specific antigen and the other to immune cells to activate host immune responses. In addition, the development of trispecific antibodies has led to further enhancement of therapeutic specificity and effects. Indeed, a variety of structurally engineered antibodies have proven effective in tumor therapy. This article provides insights into the clinical translation of emerging antibody constructs, firstly describing conventional T cell‐redirecting bispecific antibodies and subsequently discussing the application of bispecific and trispecific antibody constructs based on innate immune cell recruitment. Finally, bispecific antibodies against mutant p53 and KRAS that have been actively studied in cancer treatment are introduced.

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Engineering of a trispecific tumor-targeted immunotherapy incorporating 4-1BB co-stimulation and PD-L1 blockade

Cited by 18 publications

References 61 publications

The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner

The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner

4-1BB: A promising target for cancer immunotherapy

Emerging Antibodies in Cancer Therapy

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