Generation and preclinical characterization of an antibody specific for SEMA4D

Fisher, Terrence L.; Reilly, Christine; Winter, Laurie A.; Pandina, Tracy; Jonason, Alan S.; Scrivens, Maria; Balch, Leslie; Bussler, Holm; Torno, Sebold; Seils, Jennifer; Mueller, Loretta; Huang, He; Klimatcheva, Ekaterina; Howell, Alan; Kirk, Renee; Evans, Elizabeth E.; Paris, Mark; Leonard, John E.; Em, Smith; Zauderer, Maurice

doi:10.1080/19420862.2015.1102813

Cited by 40 publications

(31 citation statements)

References 47 publications

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“…Antibodies are known for their large ''binding footprint'' and are promising in their inhibitory potential on ligand-receptor interactions. However, obtaining specific antibodies reactive with the functional interfaces on semaphorins and plexins, which are highly conserved across species, is generally very difficult and only a few examples have been reported (Fisher et al, 2016;Yamashita et al, 2015). In contrast, midsized drugs have gained much recent attention because of their ability to bear high affinity and specificity due to their similar binding surface area to antibodies, while being free from the dependence on the immune system (Gao et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide

Matsunaga

Bashiruddin

Kitago

et al. 2016

Cell Chemical Biology

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Semaphorin axonal guidance factors are multifunctional proteins that play important roles in immune response, cancer cell proliferation, and organogenesis, making semaphorins and their signaling receptor plexins important drug targets for various diseases. However, the large and flat binding surface of the semaphorin-plexin interaction interface is difficult to target by traditional small-molecule drugs. Here, we report the discovery of a high-affinity plexin B1 (PlxnB1)-binding macrocyclic peptide, PB1m6 (K = 3.5 nM). PB1m6 specifically inhibited the binding of physiological ligand semaphorin 4D (Sema4D) in vitro and completely suppressed Sema4D-induced cell collapse. Structural studies revealed that PB1m6 binds at a groove between the fifth and sixth blades of the sema domain in PlxnB1 distant from the Sema4D-binding site, indicating the non-competitive and allosteric nature of the inhibitory activity. The discovery of this novel allosteric site can potentially be used to target plexin family proteins for the development of drugs that modulate semaphorin and plexin signaling.

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Section: Introductionmentioning

confidence: 99%

Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide

Matsunaga

Bashiruddin

Kitago

et al. 2016

Cell Chemical Biology

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“…28,73 In general, effective silencing of Sema4D in cancer cells inhibits tumor vasculature and tumor burden. 10,[74][75][76][77][78][79][80] Moreover, Sema4D activity in cancer can be targeted with monoclonal antibodies, such as VX15/2503, [81][82][83][84] currently in clinical trials for treating solid tumors. Notably, blocking Sema4D with monoclonal antibodies in tumors may promote immune cell infiltration and enhance response to immunomodulatory drugs such as anti-CTLA-4.…”

Section: Transmembrane Semaphorins In Embryo Developmentmentioning

confidence: 98%

Transmembrane semaphorins: Multimodal signaling cues in development and cancer

Gurrapu

Tamagnone

2016

Cell Adhesion & Migration

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Semaphorins constitute a large family of membrane-bound and secreted proteins that provide guidance cues for axon pathfinding and cell migration. Although initially discovered as repelling cues for axons in nervous system, they have been found to regulate cell adhesion and motility, angiogenesis, immune function and tumor progression. Notably, semaphorins are bifunctional cues and for instance can mediate both repulsive and attractive functions in different contexts. While many studies focused so far on the function of secreted family members, class 1 semaphorins in invertebrates and class 4, 5 and 6 in vertebrate species comprise around 14 transmembrane semaphorin molecules with emerging functional relevance. These can signal in juxtacrine, paracrine and autocrine fashion, hence mediating long and short range repulsive and attractive guidance cues which have a profound impact on cellular morphology and functions. Importantly, transmembrane semaphorins are capable of bidirectional signaling, acting both in "forward" mode via plexins (sometimes in association with receptor tyrosine kinases), and in "reverse" manner through their cytoplasmic domains. In this review, we will survey known molecular mechanisms underlying the functions of transmembrane semaphorins in development and cancer.

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“…In addition, semaphorins have been recently pointed as the center for new therapeutic strategies using blocking antibodies. For example, the VX15/2503, an anti-Sema4D antibody has been characterized for clinical development on MS, Huntington's disease, and cancer [157]. LaGanke et al carried out a phase 1 study providing evidence that the VX15/2503 antisemaphorin 4D antibody administered at various doses was safe and tolerated in patients with MS [158].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Roles of Semaphorins in Neurodegenerative Diseases

Quintremil¹,

Ferrer²,

Puente³

et al. 2019

Neurons - Dendrites and Axons

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Semaphorins are secreted and transmembrane proteins that bind plexin/ neuropilin or integrin receptors, providing paracrine axonal guidance signals and ultimately leading to a functional and developed neuronal network. Following semaphorin's initial discovery, their relevance in the central nervous system (CNS) soon intrigued researchers about the possible links between semaphorins, their receptors and signaling mechanisms and different neurodegenerative diseases. Here, we explore the current knowledge of semaphorin's function and signaling in Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We focus on the effects of the most known semaphorin subclasses 3A and 4D, yet extending our discussion to other semaphorins that have been found involved in specific neuropathologies and the potential effect of semaphorins modulating the immune system in disorders with inflammatory components. Molecular, cellular, and genetic evidences are reviewed, highlighting the relevance of semaphorins on each disease etiology, pathophysiology, and progression. The newly discovered semaphorin functions in neurological disorders even suggest alternative therapies that may be highly valuable in diseases that have no current cure.

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Generation and preclinical characterization of an antibody specific for SEMA4D

Cited by 40 publications

References 47 publications

Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide

Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide

Transmembrane semaphorins: Multimodal signaling cues in development and cancer

Roles of Semaphorins in Neurodegenerative Diseases

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