Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity

Hangiu, Oana; Compte, Marta; Dinesen, Anders; Navarro, Rocío; Tapia-Galisteo, Antonio; Mandrup, Ole Aalund; Erce-Llamazares, Ainhoa; Lázaro-Gorines, Rodrigo; Nehme-Álvarez, Daniel; Domínguez-Alonso, Carmen; Harwood, Seandean L.; Alfonso, Carlos; Blanco, Belén; Rubio‐Pérez, Laura; Jiménez-Reinoso, Anaïs; Díez-Alonso, Laura; Blanco, Francisco J.; Sanz, Laura; Howard, Kenneth A.; Álvarez‐Vallina, Luís

doi:10.1016/j.isci.2022.104958

Cited by 8 publications

(8 citation statements)

References 36 publications

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“…The 4-1BB receptor is expressed mainly in the cells of the immune system and belongs to the tumor necrosis factor (TNF) receptor family but has also been shown to be expressed in tumor cells [104,105]. In cancer, it has been shown that anti-4-1BB-agonistic IgG can reduce the growth of tumors [106]. In contrast, the 4-1BB protein is involved in the regulation of monocytes/macrophages in the tumor microenvironment [107].…”

Section: Discussionmentioning

confidence: 99%

Delivery of Melittin as a Lytic Agent via Graphene Nanoparticles as Carriers to Breast Cancer Cells

Daniluk

Lange

Pruchniewski

et al. 2022

JFB

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Melittin, as an agent to lyse biological membranes, may be a promising therapeutic agent in the treatment of cancer. However, because of its nonspecific actions, there is a need to use a delivery method. The conducted research determined whether carbon nanoparticles, such as graphene and graphene oxide, could be carriers for melittin to breast cancer cells. The studies included the analysis of intracellular pH, the potential of cell membranes, the type of cellular transport, and the expression of receptor proteins. By measuring the particle size, zeta potential, and FT-IT analysis, we found that the investigated nanoparticles are connected by electrostatic interactions. The level of melittin encapsulation with graphene was 86%, while with graphene oxide it was 78%. A decrease in pHi was observed for all cell lines after administration of melittin and its complex with graphene. The decrease in membrane polarization was demonstrated for all lines treated with melittin and its complex with graphene and after exposure to the complex of melittin with graphene oxide for the MDA-MB-231 and HFFF2 lines. The results showed that the investigated melittin complexes and the melittin itself act differently on different cell lines (MDA-MB-231 and MCF-7). It has been shown that in MDA-MD-231 cells, melittin in a complex with graphene is transported to cells via caveolin-dependent endocytosis. On the other hand, the melittin–graphene oxide complex can reach breast cancer cells through various types of transport. Other differences in protein expression changes were also observed for tumor lines after exposure to melittin and complexes.

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Section: Discussionmentioning

confidence: 99%

Delivery of Melittin as a Lytic Agent via Graphene Nanoparticles as Carriers to Breast Cancer Cells

Daniluk

Lange

Pruchniewski

et al. 2022

JFB

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“… 46 In this sense, the AxF (scFv) 2 here described, with a molecular weight of 55 kDa, may offer a competitive advantage in terms of tumor penetration and therefore increased therapeutic effect. Undoubtedly, it comes at the cost of faster clearance, which can be ameliorated using half-life extension strategies, such as fusion to anti-albumin binding domains, 47 albumin fragments 48 or even modifying T cells for endogenous secretion of the AxF (scFv) 2 . 49 Transduction of T cells with the corresponding gene could circumvent the need for continuous antibody administration and enable expression locally at the tumor site.…”

Section: Discussionmentioning

confidence: 99%

Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-β and PD-L1 enhances antitumor responses

Tapia-Galisteo,

Sánchez-Rodríguez,

Narbona

et al. 2024

OncoImmunology

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T cell-based immunotherapies for solid tumors have not achieved the clinical success observed in hematological malignancies, partially due to the immunosuppressive effect promoted by the tumor microenvironment, where PD-L1 and TGF-β play a pivotal role. However, durable responses to immune checkpoint inhibitors remain limited to a minority of patients, while TGF-β inhibitors have not reached the market yet. Here, we describe a bispecific antibody for dual blockade of PD-L1 and TFG-β, termed AxF (scFv) 2 , under the premise that combination with T cell redirecting strategies would improve clinical benefit. The AxF (scFv) 2 antibody was well expressed in mammalian and yeast cells, bound both targets and inhibited dose-dependently the corresponding signaling pathways in luminescence-based cellular reporter systems. Moreover, combined treatment with trispecific T-cell engagers (TriTE) or CAR-T cells significantly boosted T cell activation status and cytotoxic response in breast, lung and colorectal (CRC) cancer models. Importantly, the combination of an EpCAMxCD3×EGFR TriTE with the AxF (scFv) 2 delayed CRC tumor growth in vivo and significantly enhanced survival compared to monotherapy with the trispecific antibody. In summary, we demonstrated the feasibility of concomitant blockade of PD-L1 and TGF-β by a single molecule, as well as its therapeutic potential in combination with different T cell redirecting agents to overcome tumor microenvironment-mediated immunosuppression.

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“…It should of course be noted that antigen-binding domains can be combined in numerous other ways than those listed above, as previously described ( Brinkmann and Kontermann, 2017 ). A potential drawback from fragment-based bsAbs is their faster clearance due to the small size and lack of FcRn binding regions, however, the clearance issue has been addressed for certain applications and formats by coupling of the bsAb to HSA ( McDonagh et al, 2012 ; Mandrup et al, 2021 ; Hangiu et al, 2022 ) or including an anti-HSA antibody fragment ( Austin et al, 2021 ; Edwards et al, 2022 ; Ishiwatari-Ogata et al, 2022 ).…”

Section: The Role Of Fcmentioning

confidence: 99%

Design and engineering of bispecific antibodies: insights and practical considerations

Madsen,

Pedersen,

Kristensen

et al. 2024

Front. Bioeng. Biotechnol.

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Bispecific antibodies (bsAbs) have attracted significant attention due to their dual binding activity, which permits simultaneous targeting of antigens and synergistic binding effects beyond what can be obtained even with combinations of conventional monospecific antibodies. Despite the tremendous therapeutic potential, the design and construction of bsAbs are often hampered by practical issues arising from the increased structural complexity as compared to conventional monospecific antibodies. The issues are diverse in nature, spanning from decreased biophysical stability from fusion of exogenous antigen-binding domains to antibody chain mispairing leading to formation of antibody-related impurities that are very difficult to remove. The added complexity requires judicious design considerations as well as extensive molecular engineering to ensure formation of high quality bsAbs with the intended mode of action and favorable drug-like qualities. In this review, we highlight and summarize some of the key considerations in design of bsAbs as well as state-of-the-art engineering principles that can be applied in efficient construction of bsAbs with diverse molecular formats.

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Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity

Cited by 8 publications

References 36 publications

Delivery of Melittin as a Lytic Agent via Graphene Nanoparticles as Carriers to Breast Cancer Cells

Delivery of Melittin as a Lytic Agent via Graphene Nanoparticles as Carriers to Breast Cancer Cells

Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-β and PD-L1 enhances antitumor responses

Design and engineering of bispecific antibodies: insights and practical considerations

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