Trifunctional antibodies (trAbs) are promising novel anticancer biologics with a particular mode of action capable of linking innate with adaptive immunity. Based on their unique structure, trifunctional IgG-like heterodimeric antibodies, consisting of nonhuman mouse and rat immunoglobulin halves are able to redirect T lymphocytes, as well as accessory cells, to the tumor site. This recruitment of immune cells is accompanied by cellular activation events elicited by anti-CD3, as well as Fcγ-receptor engagement of trAbs supported by a proinflammatory Th1-biased cytokine milieu. All necessary immunological factors required for long-term vaccination-like effects are stimulated along trAb-mediated therapeutic interventions. Thus, the concerted interplay of antibody-dependent cellular cytotoxicity plus the polyclonal T-cell cytotoxicity and Fcγ-receptor-driven induction of long-lasting immune responses after the initial tumor cell elimination represent the major hallmarks of trAb-mediated treatment of malignant diseases.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.2217/fon.11.138 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery and preclinical evaluation of BPB-101: a novel triple functional bispecific antibody targeting GARP-TGF-β complex/SLC, free TGF-β and PD-L1.
Front Immunol
December 2024
The R&D Department of Betta Biologic, Betta Pharmaceuticals Co. Ltd, Hangzhou, Zhejiang, China.
Background: In the tumor microenvironment (TME), the transforming growth factor-β (TGF-β) and programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling axes are complementary, nonredundant immunosuppressive signaling pathways. Studies have revealed that active TGF-β is mainly released from the glycoprotein A repetitions predominant (GARP)-TGF-β complex on the surface of activated regulatory T cells (Tregs), B cells, natural killer (NK) cells, and tumor cells. The currently available antibodies or fusion proteins that target TGF-β are limited in their abilities to simultaneously block TGF-β release and neutralize active TGF-β in the TME, thus limiting their antitumor effects.
View Article and Find Full Text PDFImprovement of tumor-to-blood ratio of radioimmunoconjugates by poly(ethyleneimine)-containing chelating agent.
Ann Nucl Med
November 2024
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
Objective: Monoclonal antibody (mAb)-based radioimmunoconjugates (RICs) exhibit marked tumor uptake in cancer imaging and therapy, although their high blood retention has limited the development of RICs. In our previous study, a trifunctional chelating agent with a cationic poly(ethyleneimine) (PEI) structure of tetraethylenepentamine (PEI4), maleimide-DOTA-PEI4 (MDI4), improved the tumor-to-blood ratio of RICs by increasing tumor retention compared with a conventional bifunctional chelating agent. In this study, we developed a novel chelating agent composed of a maleimide moiety, DOTA derivative, and two PEI4 structures as a PEI4-2 unit, maleimide-DOTA-PEI4-2 (MDI4-2), a design for a highly cationized chelating agent to synthesize RICs.
View Article and Find Full Text PDFExploration of Solid Phase Peptoid Synthesis for the Design of Trifunctional Hapten-Lipid-TLR7/8 Agonist Antibody-Recruiting Oligomers That Combine Innate Effector with Innate Activation Function.
ACS Appl Bio Mater
January 2025
Department of Pharmaceutics, Ghent University, Ghent 9000, Belgium.
The strategic engagement of innate immunity is a promising avenue for cancer treatment. Antibody-recruiting molecules (ARMs) direct endogenous antibodies to target tumor sites, eliciting innate immune effector killing responses. In this study, we report the synthesis of ARMs by employing solid-phase peptoid synthesis to construct three libraries of antibody-recruiting oligomers.
View Article and Find Full Text PDFA first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different elements.
Chem Sci
July 2024
The University of Sydney, School of Medical Sciences New South Wales 2006 Australia
A covalent adduct of DFOB and DOTA separated by a l-lysine residue (DFOB-l-Lys- -DOTA) exhibited remarkable regioselective metal binding, with {H}-C NMR spectral shifts supporting Zr(iv) coordinating to the DFOB unit, and Lu(iii) coordinating to the DOTA unit. This first-in-class, dual-chelator theranostic design could enable the use of imaging-therapy radiometal pairs of different elements, such as Zr for positron emission tomography (PET) imaging and Lu for low-energy β-particle radiation therapy. DFOB-l-Lys- -DOTA was elaborated with an amine-terminated polyethylene glycol extender unit (PEG4) to give DFOB- -(PEG4)-l-Lys- -DOTA (compound D2) to enable installation of a phenyl-isothiocyanate group (Ph-NCS) for subsequent monoclonal antibody (mAb) conjugation (mAb = HuJ591).
View Article and Find Full Text PDFSynthesis and Evaluation of a Cathepsin B-Recognizing Trifunctional Chelating Agent to Improve Tumor Retention of Radioimmunoconjugates.
J Labelled Comp Radiopharm
June 2024
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Cathepsin B (CTSB) is a lysosomal protease that is overexpressed in tumor cells. Radioimmunoconjugates (RICs) composed of CTSB-recognizing chelating agents are expected to increase the molecular weights of their radiometabolites by forming conjugates with CTSB in cells, resulting in their improved retention in tumor cells. We designed a novel CTSB-recognizing trifunctional chelating agent, azide-[In]In-DOTA-CTSB-substrate ([In]In-ADCS), to synthesize a RIC, trastuzumab-[In]In-ADCS ([In]In-TADCS), and evaluated its utility to improve tumor retention of the RIC.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!