6NMS

Blocking Fab 136 anti-SIRP-alpha antibody in complex with SIRP-alpha Variant 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Discovery of high affinity, pan-allelic, and pan-mammalian reactive antibodies against the myeloid checkpoint receptor SIRP alpha.

Sim, J.Sockolosky, J.T.Sangalang, E.Izquierdo, S.Pedersen, D.Harriman, W.Wibowo, A.S.Carter, J.Madan, A.Doyle, L.Harrabi, O.Kauder, S.E.Chen, A.Kuo, T.C.Wan, H.Pons, J.

(2019) MAbs 11: 1036-1052

  • DOI: https://doi.org/10.1080/19420862.2019.1624123
  • Primary Citation of Related Structures:  
    6NMR, 6NMS, 6NMT, 6NMU, 6NMV

  • PubMed Abstract: 

    Targeting the CD47-signal-regulatory protein α (SIRPα) 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, SIRPα expression is mainly restricted to myeloid cells and neurons. Therefore, compared to CD47-targeted therapies, targeting SIRPα may result in differential safety and efficacy profiles, potentially enabling lower effective doses and improved pharmacokinetics and pharmacodynamics. The development of effective SIRPα antagonists is restricted by polymorphisms within the CD47-binding domain of SIRPα, necessitating pan-allele reactive anti-SIRPα antibodies for therapeutic intervention in diverse patient populations. We immunized wild-type and human antibody transgenic chickens with a multi-allele and multi-species SIRPα regimen in order to discover pan-allelic and pan-mammalian reactive anti-SIRPα antibodies suitable for clinical translation. A total of 200 antibodies were isolated and screened for SIRPα reactivity from which approximately 70 antibodies with diverse SIRPα binding profiles, sequence families, and epitopes were selected for further characterization. A subset of anti-SIRPα antibodies bound to both human SIRPα v1 and v2 alleles with high affinity ranging from low nanomolar to picomolar, potently antagonized the CD47/SIRPα interaction, and potentiated macrophage-mediated antibody-dependent cellular phagocytosis in vitro . X-ray crystal structures of five anti-SIRPα antigen-binding fragments, each with unique epitopes, in complex with SIRPα (PDB codes 6NMV, 6NMU, 6NMT, 6NMS, and 6NMR) are reported. Furthermore, some of the anti-SIRPα antibodies cross-react with cynomolgus SIRPα and various mouse SIRPα 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-SIRPα 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; FcγR: Fcγ receptor; Ig: immunoglobulin; IND: investigational new drug; MDM⊘: monocyte-derived macrophage; NOD: non-obese diabetic; scFv: single chain fragment variable; SCID: severe combined immunodeficiency; SIRP: signal-regulatory protein.


  • Organizational Affiliation

    a ALX Oncology, Departments of Protein Sciences and Translational Biology , Burlingame , CA , USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fab 136 anti-SIRP-alpha antibody Variable Light ChainA [auth L],
D [auth A]
215Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Fab 136 anti-SIRP-alpha antibody Variable Heavy ChainB [auth H],
E [auth B]
228Homo sapiensMutation(s): 0 
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein phosphatase non-receptor type substrate 1C [auth S],
F [auth C]
127Homo sapiensMutation(s): 0 
Gene Names: SIRPABITMFRMYD1PTPNS1SHPS1SIRP
UniProt & NIH Common Fund Data Resources
Find proteins for P78324 (Homo sapiens)
Explore P78324 
Go to UniProtKB:  P78324
PHAROS:  P78324
GTEx:  ENSG00000198053 
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UniProt GroupP78324
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.39α = 90
b = 75.19β = 104.43
c = 103.82γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
PHENIXrefinement
PDB_EXTRACTdata extraction
autoPROCdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-08-07
    Type: Initial release
  • Version 1.1: 2019-08-14
    Changes: Data collection, Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Refinement description