Synthesis and evaluation of anti-PD-L1-B11 antibody fragments for PET imaging of PD-L1 in breast cancer and melanoma tumor models.

There is a critical need to non-invasively assess the PD-L1 expression in tumors as a predictive biomarker for determining the efficacy of anti-PD-1/PD-L1 immunotherapies. Non-invasive imaging modality like positron emission tomography (PET) can be a powerful tool to assess the PD-L1 expression in the whole body including multiple metastases as a patient selection criterion for the anti-PD-1/PD-L1 immunotherapy. In this study, we synthesized B11-nanobody, B11-scFv and B11-diabody fragments from the full-length anti-PD-L1 B11 IgG.

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance.

ADAM10 and ADAM17 expression and soluble PD-L1 (sPD-L1) predict poor prognosis in many malignancies, including in patients treated with PD-(L)1 inhibitors. The mechanism of soluble PD-L1 production and its effects are unknown. Here we uncover a novel mechanism of ADAM10- and ADAM17-mediated resistance to PD-(L)1 inhibitors.

A comparison of human natural monoclonal antibodies and aptamer conjugates for promotion of CNS remyelination: where are we now and what comes next?

Introduction: Multiple sclerosis (MS) is a chronic and progressive inflammatory demyelinating disease of the human central nervous system (CNS) and is the most common disabling neurological condition in young adults, resulting in severe neurological defects. No curative or long-term progression-inhibiting therapy has yet been developed. However, recent investigation has revealed potential strategies that do not merely modulate potentially pathogenic autoimmune responses, but stimulate remyelination within CNS lesions.

Treatment with a recombinant human IgM that recognizes PSA-NCAM preserves brain pathology in MOG-induced experimental autoimmune encephalomyelitis.

A single peripheral dose of CNS-binding IgMs promote remyelination and preserve axons in a number of animal models of neurologic disease. A myelin-binding recombinant human IgM (rHIgM22) is presently in a safety trial in MS patients following an acute MS exacerbation. rHIgM22 (directed against oligodendrocytes) or rHIgM12 (directed against neurons) were administered to mice with MOG-induced experimental autoimmune encephalomyelitis (EAE) with study endpoints: clinical deficits and brain and spinal cord pathology.

Human class I major histocompatibility complex alleles determine central nervous system injury versus repair.

Background: We investigated the role of human HLA class I molecules in persistent central nervous system (CNS) injury versus repair following virus infection of the CNS.

Methods: Human class I A11 and B27 transgenic human beta-2 microglobulin positive (Hβ2m) mice of the H-2 background were generated on a combined class I-deficient (mouse beta-2 microglobulin deficient, β2m) and class II-deficient (mouse Aβ) phenotype. Intracranial infection with Theiler's murine encephalomyelitis virus (TMEV) in susceptible SJL mice results in acute encephalitis with prominent injury in the hippocampus, striatum, and cortex.

Multiple Sclerosis, Gut Microbiota and Permeability: Role of Tryptophan Catabolites, Depression and the Driving Down of Local Melatonin.

Background: Alterations in gut microbiota, coupled to increased gut permeability are now widely recognized as having a role in the etiology, course and treatment of many medical conditions, including autoimmune and neurodegenerative disorders.

Methods: In this review, the role that such gut changes play over the course of multiple sclerosis (MS) is detailed.

Results: Given the wide array of biological factors and processes that have been shown to be altered in MS, including changes in the gut, this allows for a better integration of the diverse array of pathophysiological processes linked to MS.

Concomitant Use of Neuroprotective Drugs in Neuro Rehabilitation of Multiple Sclerosis.

We provide an overview of rehabilitation in neurological diseases. A large amount of literature available on neurorehabilitation is based from the rehabilitative work on stroke and spinal cord injuries. After a brief description of rehabilitation, the potential application of neurorehabilitation in neurodegenerative diseases specifically multiple sclerosis (MS) is summarized.

A human anti-polysialic acid antibody as a potential treatment to improve function in multiple sclerosis patients.

We previously identified a human monoclonal antibody, termed HIgM12 that stimulates spontaneous locomotor activity in a chronically demyelinating mouse model of multiple sclerosis. When tested as a molecular substrate, HIgM12 stimulated neurite outgrowth . We recently reported that polysialic acid (PSA) attached to the neural cell adhesion molecule (NCAM) is one of the cellular antigens for HIgM12.

Antibody Binding Specificity for Kappa (Vκ) Light Chain-containing Human (IgM) Antibodies: Polysialic Acid (PSA) Attached to NCAM as a Case Study.

Antibodies of the IgM isotype are often neglected as potential therapeutics in human trials, animal models of human diseases as well as detecting agents in standard laboratory techniques. In contrast, several human IgMs demonstrated proof of efficacy in cancer models and models of CNS disorders including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Reasons for their lack of consideration include difficulties to express, purify and stabilize IgM antibodies, challenge to identify (non-protein) antigens, low affinity binding and fundamental knowledge gaps in carbohydrate and lipid research.

A monoclonal natural human IgM protects axons in the absence of remyelination.

Background: Whereas demyelination underlies early neurological symptoms in multiple sclerosis (MS), axonal damage is considered critical for permanent chronic deficits. Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic induced demyelinating disease (TMEV-IDD) with progressive axonal loss and neurologic dysfunction similar to progressive forms of MS. We previously reported that treatment of chronic TMEV-IDD mice with a neurite outgrowth-promoting natural human antibody, HIgM12, improved brainstem NAA concentrations and preserved functional motor activity.

Generation of Catalytic Antibodies Is an Intrinsic Property of an Individual's Immune System: A Study on a Large Cohort of Renal Transplant Patients.

Renal transplant is the treatment of choice for patients with terminal end-stage renal disease. We have previously identified low levels of catalytic IgG as a potential prognosis marker for chronic allograft rejection. The origin and physiopathological relevance of catalytic Abs is not well understood, owing to the fact that catalytic Abs have been studied in relatively small cohorts of patients with rare diseases and/or without systematic follow-up.

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis.

Introduction: Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the CNS and results in neurological disability. Existing immunomodulatory and immunosuppressive approaches lower the number of relapses but do not cure or reverse existing deficits nor improve long-term disability in MS patients.

Areas Covered: Monogenic antibodies were described as treatment options for MS, however the immunogenicity of mouse antibodies hampered the efficacy of potential therapeutics in humans.

Tryptophan Catabolites and Their Impact on Multiple Sclerosis Progression.

Accumulating evidence demonstrates involvement of tryptophan metabolites and in particular activation of the kynurenine pathway (KP) in neurocognitive disorders under CNS inflammatory conditions. The KP is involved in several brain-associated disorders including Parkinson's disease, AIDS dementia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, schizophrenia, and brain tumors. Our review is an attempt to address any relevant association between dysregulation of KP and multiple sclerosis (MS), an inflammatory CNS disorder that ultimately leads to demyelinated brain areas and severe neurological deficits.

Tryptophan Metabolites and Their Impact on Multiple Sclerosis Progression.

Accumulating evidence demonstrates involvement of tryptophan metabolites and in particular activation of the kynurenine pathway (KP) in neurocognitive disorders under CNS inflammatory conditions. The KP is involved in several brain-associated disorders including Parkinson's disease, AIDS dementia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, schizophrenia, and brain tumors. Our review is an attempt to address any relevant association between dysregulation of KP and multiple sclerosis (MS), an inflammatory CNS disorder that ultimately leads to demyelinated brain areas and severe neurological deficits.

Antibody-Mediated Oligodendrocyte Remyelination Promotes Axon Health in Progressive Demyelinating Disease.

Demyelination underlies early neurological symptoms in multiple sclerosis (MS); however, axonal damage is considered critical for permanent chronic deficits. The precise mechanisms by which axonal injury occurs in MS are unclear; one hypothesis is the absence or failure of remyelination, suggesting that promoting remyelination may protect axons from death. This report provides direct evidence that promoting oligodendrocyte remyelination protects axons and maintains transport function.

Naturally Occurring Monoclonal Antibodies and Their Therapeutic Potential for Neurologic Diseases.

Importance: Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases.

Objective: To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders.

A natural human IgM that binds to gangliosides is therapeutic in murine models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurological disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 µg intraperitoneal dose of rHIgM12 increases survival in two independent genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10 days, delays the onset of neurological deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons.

Abbreviated exposure to hypoxia is sufficient to induce CNS dysmyelination, modulate spinal motor neuron composition, and impair motor development in neonatal mice.

Neonatal white matter injury (nWMI) is an increasingly common cause of cerebral palsy that results predominantly from hypoxic injury to progenitor cells including those of the oligodendrocyte lineage. Existing mouse models of nWMI utilize prolonged periods of hypoxia during the neonatal period, require complex cross-fostering and exhibit poor growth and high mortality rates. Abnormal CNS myelin composition serves as the major explanation for persistent neuro-motor deficits.

A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis.

Background: Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12.

Polysialic acid as an antigen for monoclonal antibody HIgM12 to treat multiple sclerosis and other neurodegenerative disorders.

CNS regeneration is a desirable goal for diseases of brain and spinal cord. Current therapeutic strategies for the treatment of multiple sclerosis (MS) aim to eliminate detrimental effects of the immune system, so far without reversing disability or affecting long-term prognosis in patients. Approachable molecular targets that stimulate CNS repair are not part of the clinical praxis or have not been identified yet.

Quantitative PCR analysis of DNA aptamer pharmacokinetics in mice.

DNA aptamer oligonucleotides and their protein conjugates show promise as therapeutics in animal models of diseases such as multiple sclerosis. These molecules are large and highly charged, raising questions about their biodistribution and pharmacokinetics in mammals. Here we exploit the power of quantitative polymerase chain reaction to accurately quantitate the tissue distribution of 40-nucleotide DNA aptamers and their streptavidin conjugates after intraperitoneal injection in mice.

Deletion of Virus-specific T-cells Enhances Remyelination in a Model of Multiple Sclerosis.

We used transgenic expression of capsid antigens to Theiler's murine encephalomyelitis virus (TMEV) to study how the immune response to VP1 and VP2 influences spinal cord demyelination, remyelination and axonal loss during the acute and chronic phases of infection. Expression from birth of capsid antigen under the ubiquitin promoter resulted in tolerance to the antigen and absence of an immune response to the respective capsid antigen following virus infection. The transgenic mice were crossed to B10.

Applications of SPR for the characterization of molecules important in the pathogenesis and treatment of neurodegenerative diseases.

Characterization of binding kinetics and affinity between a potential drug and its receptor are key steps in the development of new drugs. Among the techniques available to determine binding affinities, surface plasmon resonance has emerged as the gold standard because it can measure binding and dissociation rates in real-time in a label-free fashion. Surface plasmon resonance is now finding applications in the characterization of molecules for treatment of neurodegenerative diseases, characterization of molecules associated with pathogenesis of neurodegenerative diseases and detection of neurodegenerative disease biomarkers.

Cellular targets and mechanistic strategies of remyelination-promoting IgMs as part of the naturally occurring autoantibody repertoire.

Immunoglobulins with germline sequences occur in invertebrates and vertebrates and are named naturally occurring autoantibodies (NAbs). NAbs may target foreign antigens, self- or altered self-components and are part of the normal immunoglobulin repertoire. Accumulating evidence indicates that naturally occurring antibodies can act as systemic surveillance molecules, which tag, damaged or stressed cells, invading pathogens and toxic cellular debris for elimination by the immune system.