6nms | pdb_00006nms
Blocking Fab 136 anti-SIRP-alpha antibody in complex with SIRP-alpha Variant 1
Structural highlights
FunctionSHPS1_HUMAN Immunoglobulin-like cell surface receptor for CD47. Acts as docking protein and induces translocation of PTPN6, PTPN11 and other binding partners from the cytosol to the plasma membrane. Supports adhesion of cerebellar neurons, neurite outgrowth and glial cell attachment. May play a key role in intracellular signaling during synaptogenesis and in synaptic function (By similarity). Involved in the negative regulation of receptor tyrosine kinase-coupled cellular responses induced by cell adhesion, growth factors or insulin. Mediates negative regulation of phagocytosis, mast cell activation and dendritic cell activation. CD47 binding prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells.[1] [2] Publication Abstract from PubMedTargeting the CD47-signal-regulatory protein alpha (SIRPalpha) pathway represents a novel therapeutic approach to enhance anti-cancer immunity by promoting both innate and adaptive immune responses. Unlike CD47, which is expressed ubiquitously, SIRPalpha expression is mainly restricted to myeloid cells and neurons. Therefore, compared to CD47-targeted therapies, targeting SIRPalpha may result in differential safety and efficacy profiles, potentially enabling lower effective doses and improved pharmacokinetics and pharmacodynamics. The development of effective SIRPalpha antagonists is restricted by polymorphisms within the CD47-binding domain of SIRPalpha, necessitating pan-allele reactive anti-SIRPalpha antibodies for therapeutic intervention in diverse patient populations. We immunized wild-type and human antibody transgenic chickens with a multi-allele and multi-species SIRPalpha regimen in order to discover pan-allelic and pan-mammalian reactive anti-SIRPalpha antibodies suitable for clinical translation. A total of 200 antibodies were isolated and screened for SIRPalpha reactivity from which approximately 70 antibodies with diverse SIRPalpha binding profiles, sequence families, and epitopes were selected for further characterization. A subset of anti-SIRPalpha antibodies bound to both human SIRPalpha v1 and v2 alleles with high affinity ranging from low nanomolar to picomolar, potently antagonized the CD47/SIRPalpha interaction, and potentiated macrophage-mediated antibody-dependent cellular phagocytosis in vitro. X-ray crystal structures of five anti-SIRPalpha antigen-binding fragments, each with unique epitopes, in complex with SIRPalpha (PDB codes 6NMV, 6NMU, 6NMT, 6NMS, and 6NMR) are reported. Furthermore, some of the anti-SIRPalpha antibodies cross-react with cynomolgus SIRPalpha and various mouse SIRPalpha alleles (BALB/c, NOD, BL/6), which can facilitate preclinical to clinical development. These properties provide an attractive rationale to advance the development of these anti-SIRPalpha antibodies as a novel therapy for advanced malignancies. Abbreviations: ADCC: antibody-dependent cellular cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; CFSE: carboxyfluorescein succinimidyl ester; Fab: fragment antigen binding; Fc: fragment crystallizable; FcgammaR: Fcgamma receptor; Ig: immunoglobulin; IND: investigational new drug; MDM solidus in circle: monocyte-derived macrophage; NOD: non-obese diabetic; scFv: single chain fragment variable; SCID: severe combined immunodeficiency; SIRP: signal-regulatory protein. Discovery of high affinity, pan-allelic, and pan-mammalian reactive antibodies against the myeloid checkpoint receptor SIRPalpha.,Sim J, Sockolosky JT, Sangalang E, Izquierdo S, Pedersen D, Harriman W, Wibowo AS, Carter J, Madan A, Doyle L, Harrabi O, Kauder SE, Chen A, Kuo TC, Wan H, Pons J MAbs. 2019 Aug/Sep;11(6):1036-1052. doi: 10.1080/19420862.2019.1624123. Epub 2019, Jul 1. PMID:31257988[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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