Antibody-cytokine fusion proteins: A novel class of biopharmaceuticals for the therapy of cancer and of chronic inflammation

Murer, Patrizia; Neri, Dario

doi:10.1016/j.nbt.2019.04.002

Cited by 73 publications

(57 citation statements)

References 195 publications

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“…In addition to non-targeted GITR agonists, efforts are being made to develop tumor-targeted GITRL fusion proteins 11,16 , since there is evidence that the local delivery of GITR agonists can improve the therapeutic activity of GITR agonists 17 . Our group has worked for the last two decades on the antibody-based delivery of cytokine payloads to tumors and has characterized more than 100 fusion proteins until now 18 , but had never worked before with GITRL payloads.…”

Section: Researchers At Apogenix Have Developed a Fusion Protein Of Amentioning

confidence: 99%

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

Mock

Rascon

Stringhini

et al. 2020

Preprint

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Preclinical evidence has suggested that the Glucocorticoid-Induced TNFR-related protein (GITR) may be valuable a target for the development of anticancer therapeutics, but clinical studies with GITR ligand (GITRL) have been disappointing. Here, we report the development of a fusion protein featuring GITR ligand (GITRL) fused to the F8 antibody which targets the alternatively-spliced EDA domain of fibronectin, a tumor-associated antigen often found around the tumor neovasculature. Five different formats for F8-GITRL fusion proteins were cloned and characterized, but quantitative biodistribution studies failed to evidence a preferential accumulation at the tumor site. The in vivo tumor targeting properties of F8-GITRL could be substantially improved by enzymatic deglycosylation or site-directed mutagenesis of the N-glycosylation consensus sequence. However, therapy studies in a murine model of cancer with the glycoengineered F8-GITRL N74S and N157T variant failed to elicit a durable anti-tumor response, both in monotherapy and in combination with PD-1 blockade.HIGHLIGHTSDifferent formats of fusion proteins featuring Glucocorticoid-induced TNFR-related protein ligand (GITRL) fused to a tumor-targeting antibody were produced.The tumor uptake of the fusion proteins could be increased by enzymatic deglycosylation of the fusion protein or by site-directed mutagenesis of the N-glycosylation consensus sequences.The fusion protein developed in this study failed to show any anti-tumor activity either alone or in combination with PD-1 inhibition.

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Section: Researchers At Apogenix Have Developed a Fusion Protein Of Amentioning

confidence: 99%

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

Mock

Rascon

Stringhini

et al. 2020

Preprint

Self Cite

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“…Cytokines are immunomodulatory proteins, which have been considered for pharmaceutical applications for the treatment of cancer patients [1][2][3] and other types of disease 2 . There is a growing interest in the use of engineered cytokine products as anti-cancer drugs, capable of boosting the action of T cells and natural killer (NK) cells against tumors 3,4 , alone or in combination with immune check-point inhibitors 3,[5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

“…Alternatively, tumor-homing antibody fusions have been developed, since the preferential concentration of cytokine payloads at the tumor site has been shown in preclinical models to potentiate therapeutic activity, helping spare normal tissues [28][29][30][31][32][33][34] . Various antibody-cytokine fusions are currently being investigated in clinical trials for the treatment of cancer and of chronic inflammatory conditions [for reviews, see 2,33,[35][36][37] ]. Antibody-cytokine fusions display biological activity immediately after injection to patients, which may lead to unwanted toxicity and prevent escalation to therapeutically active dose regimens 9,22,38 .…”

Section: Introductionmentioning

confidence: 99%

An engineered 4-1BBL fusion protein with “activity-on-demand”

Mock

Stringhini

Villa

et al. 2020

Preprint

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ABSTRACTEngineered cytokines are gaining importance for cancer therapy but those products are often limited by toxicity, especially at early time points after intravenous administration. 4-1BB is a member of the tumor necrosis factor receptor superfamily, which has been considered as a target for therapeutic strategies with agonistic antibodies or using its cognate cytokine ligand, 4-1BBL. Here we describe the engineering of an antibody fusion protein (termed F8-4-1BBL), which does not exhibit cytokine activity in solution but regains biological activity upon antigen binding. F8-4-1BBL bound specifically to its cognate antigen, the alternatively-spliced EDA domain of fibronectin, and selectively localized to tumors in vivo, as evidenced by quantitative biodistribution experiments. The product promoted a potent anti-tumor activity in various mouse models of cancer, without apparent toxicity at the doses used. F8-4-1BBL represents a prototype for antibody-cytokine fusion proteins, which conditionally display “activity-on-demand” properties at the site of disease upon antigen binding and reduce toxicity to normal tissues.

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“…To increase the therapeutic efficacy of cytokine payloads, the generation of fusion proteins with tumor-homing antibodies has been proposed. Antibodycytokine fusion proteins (also termed "immunocytokines") are capable of increasing the therapeutic index of the corresponding cytokine payload, as results of a selective localization at the site of disease [24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

The immunocytokine L19-TNF eradicates Sarcomas in combination with Chemotherapy agents or with immune check-point inhibitors

Corbellari

Villa

Neri

et al. 2019

Preprint

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AbstractAntibody-cytokine fusion proteins (also called “immunocytokines”) represent an emerging class of biopharmaceutical products, which are being considered for cancer immunotherapy. When used as single agents, pro-inflammatory immunocytokines are rarely capable of induce complete and durable cancer regression in mouse models and in patients. However, the combination treatment with conventional chemotherapy or with other immune-stimulatory agents typically increases the therapeutic efficacy of immunocytokines.In this article, we describe combination treatments of a tumor-targeting antibody-cytokine fusion protein based on the L19 antibody (specific to a splice isoform of fibronectin) fused to murine tumor necrosis factor (TNF) with standard chemotherapy (dacarbazine, trabectedin or melphalan) or with an immune check-point inhibitor (anti-PD-1) in a BALB/c derived immunocompetent murine model of sarcoma (WEHI-164).All combination treatments led to improved tumor remission compared to single agent treatments, suggesting that these combination partners may be suitable for further clinical development in sarcoma patients.

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Antibody-cytokine fusion proteins: A novel class of biopharmaceuticals for the therapy of cancer and of chronic inflammation

Cited by 73 publications

References 195 publications

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

An engineered 4-1BBL fusion protein with “activity-on-demand”

The immunocytokine L19-TNF eradicates Sarcomas in combination with Chemotherapy agents or with immune check-point inhibitors

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