Synthetic antibody mimics for the inhibition of protein–ligand interactions

Haußner, Christina; Lach, Johannes; Eichler, Jutta

doi:10.1016/j.cbpa.2017.07.001

Cited by 17 publications

(21 citation statements)

References 37 publications

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“…Synthetic peptide mimics have also been derived from antibody paratopes, i.e., the regions of an antibody specifically recognizing the corresponding antigen via its complementarity-determining regions (CDRs) on the surface of the variable domain of both heavy and light chains [ 99 ]. Molecules that mimic the CDRs of an antibody can, therefore, be expected to mimic the binding specificities of the antibody and, consequently, its effect in preventing the interaction of a disease-associated protein with its ligand [ 100 ] ( Figure 6 , right). We have recently reported on paratope mimetic peptides of the broadly neutralizing HIV-1 antibody b12 [ 101 ].…”

Section: Hiv-1 Vaccine Developmentmentioning

confidence: 99%

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

Ringel

Vieillard

Debré

et al. 2018

Viruses

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Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. We discuss here the major reasons for the failure of “classical” vaccine approaches, which are mostly due to the biological properties of the virus itself. HIV-1 has developed multiple mechanisms of immune escape, which also account for vaccine failure. So far, no vaccine candidate has been able to induce broadly neutralizing antibodies (bnAbs) against primary patient viruses from different clades. However, such antibodies were identified in a subset of patients during chronic infection and were shown to protect from infection in animal models and to reduce viremia in first clinical trials. Their detailed characterization has guided structure-based reverse vaccinology approaches to design better HIV-1 envelope (Env) immunogens. Furthermore, conserved Env epitopes have been identified, which are promising candidates in view of clinical applications. Together with new vector-based technologies, considerable progress has been achieved in recent years towards the development of an effective antibody-based HIV-1 vaccine.

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Section: Hiv-1 Vaccine Developmentmentioning

confidence: 99%

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

Ringel

Vieillard

Debré

et al. 2018

Viruses

Self Cite

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“…The use of antibodies for cancer therapy takes advantage of the specific binding of antibodies to their targets and has led to the introduction of several antibody-based cancer therapeutics into the clinic (Scott et al, 2012; Sliwkowski and Mellman, 2013). Although antibodies have high specificity, limited tissue penetration and difficulties in generating large amounts of homogeneous antibody products cost-effectively initially restricted their use, and a wide range of antibody fragments, antibody-drug conjugates and antibody-like molecules have been developed to address these challenges (Casi and Neri, 2015; Weiner, 2015; Haußner et al, 2017). In particular, peptides and peptide-polymer conjugates can mimic the functions of large folded proteins such as antibodies and have the advantage that they are synthetically accessible and readily modified and optimized for specific biological functions (Ahrens et al, 2012; Fosgerau and Hoffmann, 2015; Gross et al, 2015; Conibear et al, 2017a).…”

Section: Introductionmentioning

confidence: 99%

Multifunctional Scaffolds for Assembling Cancer-Targeting Immune Stimulators Using Chemoselective Ligations

et al. 2019

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Chemoselective ligations allow chemical biologists to functionalise proteins and peptides for biomedical applications and to probe biological processes. Coupled with solid phase peptide synthesis, chemoselective ligations enable not only the design of homogeneous proteins and peptides with desired natural and unnatural modifications in site-specific locations but also the design of new peptide and protein topologies. Although several well-established ligations are available, each method has its own advantages and disadvantages and they are seldom used in combination. Here we have applied copper-catalyzed azide-alkyne “click,” oxime, maleimide, and native chemical ligations to develop a modular synthesis of branched peptide and polymer constructs that act as cancer-targeting immune system engagers (ISErs) and functionalised them for detection in biological systems. We also note some potential advantages and pitfalls of these chemoselective ligations to consider when designing orthogonal ligation strategies. The modular synthesis and functionalization of ISErs facilitates optimisation of their activity and mechanism of action as potential cancer immunotherapies.

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“…19 Fully synthetic antibody mimics are particularly attractive for biomedical applications because their structure can be tailored to increase binding affinities and selectivity, reduce immunogenicity, and lower the cost of producing antibodies. 19 However, the absence of the Fc component in antibody mimics has hindered their therapeutic applications because many important cell killing mechanisms (e.g., the complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity mechanisms) require the Fc component to activate other immune cells (e.g., T cells). 22 Selective High-Affinity Ligands (SHALs) belong to a family of fully synthetic antibody mimics that are designed in silico to bind to the Lym-1 epitope in the β-subunit of the human leukocyte antigen-D related (HLA-DR) antigen (Figures 1A and S1).…”

Section: Introductionmentioning

confidence: 99%

High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles

Balhorn

et al. 2018

ACS Cent. Sci.

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Non-Hodgkin lymphoma is one of the most common types of cancer. Relapsed and refractory diseases are still common and remain significant challenges as the majority of these patients eventually succumb to the disease. Herein, we report a translatable concurrent chemo-immuno-radiotherapy (CIRT) strategy that utilizes fully synthetic antibody mimic Selective High-Affinity Ligand (SHAL)-functionalized doxorubicin-encapsulated nanoparticles (Dox NPs) for the treatment of human leukocyte antigen-D related (HLA-DR) antigen-overexpressed tumors. We demonstrated that our tailor-made antibody mimic-functionalized NPs bound selectively to different HLA-DR-overexpressed human lymphoma cells, cross-linked the cell surface HLA-DR, and triggered the internalization of NPs. In addition to the direct cytotoxic effect by Dox, the internalized NPs then released the encapsulated Dox and upregulated the HLA-DR expression of the surviving cells, which further augmented immunogenic cell death (ICD). The released Dox not only promotes ICD but also sensitizes the cancer cells to irradiation by inducing cell cycle arrest and preventing the repair of DNA damage. In vivo biodistribution and toxicity studies confirm that the targeted NPs enhanced tumor uptake and reduced systemic toxicities of Dox. Our comprehensive in vivo anticancer efficacy studies using lymphoma xenograft tumor models show that the antibody-mimic functional NPs effectively inhibit tumor growth and sensitize the cancer cells for concurrent CIRT treatment without incurring significant side effects. With an appropriate treatment schedule, the SHAL-functionalized Dox NPs enhanced the cell killing efficiency of radiotherapy by more than 100% and eradicated more than 80% of the lymphoma tumors.

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Synthetic antibody mimics for the inhibition of protein–ligand interactions

Cited by 17 publications

References 37 publications

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

Multifunctional Scaffolds for Assembling Cancer-Targeting Immune Stimulators Using Chemoselective Ligations

High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles

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