Three-dimensional structure of an immunoglobulin light-chain dimer with amyloidogenic properties

Bourne, Philip C.; Ramsland, Paul A.; Shan, Lin; Fan, Zhao; DeWitt, C.R.; Shultz, B.B.; Terzyan, Simon; Moomaw, Carolyn R.; Slaughter, Clive A.; Guddat, L.W.; Edmundson, Allen B.

doi:10.1107/s0907444902004183

Cited by 35 publications

(33 citation statements)

References 40 publications

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“…66,67 While the presence of β-strands is not essential to form this motif, several β-rich proteins (e.g., β 2 -microglobulin, transthyretin, immunoglobulin light chain especially of type λ, immunoglobulin heavy chain, concavalin A) form amyloids using the cross-β motif as seed. [68][69][70][71][72][73] In addition, Siepen et al have shown that the exposed edge β-strands in…”

Section: Sequence Differences and Similaritiesmentioning

confidence: 99%

Potential aggregation prone regions in biotherapeutics

Wang

Das

Singh

et al. 2009

mAbs

183

139

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Aggregation of a biotherapeutic is of significant concern and judicious process and formulation development is required to minimize aggregate levels in the final product. Aggregation of a protein in solution is driven by intrinsic and extrinsic factors. In this work we have focused on aggregation as an intrinsic property of the molecule. We have studied the sequences and Fab structures of commercial and non-commercial antibody sequences for their vulnerability towards aggregation by using sequence based computational tools to identify potential aggregation-prone motifs or regions. The mAbs in our dataset contain 2 to 8 aggregation-prone motifs per heavy and light chain pair. Some of these motifs are located in variable domains, primarily in CDRs. Most aggregation-prone motifs are rich in β branched aliphatic and aromatic residues. Hydroxyl-containing Ser/Thr residues are also found in several aggregation-prone motifs while charged residues are rare. The motifs found in light chain CDR3 are glutamine (Q)/asparagine (N) rich. These motifs are similar to the reported aggregation promoting regions found in prion and amyloidogenic proteins that are also rich in Q/N, aliphatic and aromatic residues. The implication is that one possible mechanism for aggregation of mAbs may be through formation of cross-β structures and fibrils. Mapping on the available Fab-receptor/ antigen complex structures reveals that these motifs in CDRs might also contribute significantly towards receptor/antigen binding. Our analysis identifies the opportunity and tools for simultaneous optimization of the therapeutic protein sequence for potency and specificity while reducing vulnerability towards aggregation.

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Section: Sequence Differences and Similaritiesmentioning

confidence: 99%

Potential aggregation prone regions in biotherapeutics

Wang

Das

Singh

et al. 2009

mAbs

183

139

View full text Add to dashboard Cite

show abstract

“…AL amyloidosis can occur as a primary phenomenon or in association with different forms of plasma cell disorders, such as MGUS or MM [4,15], with 10%-15% of MM patients developing an AL amyloidosis of vital organs [7][8][9][10]. In AL amyloidosis, only 18% of patients have >20% plasma cells in the BM, while the majority (60%) have <10% [6].…”

Section: Al Amyloidosis Can Be Associated With MM Lc-mm and Nonsecrmentioning

confidence: 99%

Primary (AL) Amyloidosis in Plasma Cell Disorders

Müller¹,

Geibel²,

Neumann³

et al. 2006

The Oncologist

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Primary (AL) amyloidosis is the most common form of systemic amyloidosis. The morbidity arises from extracellular deposition of immunoglobulin light chain (LC) fibrils in major organs, such as the kidneys, heart, and bowel. Organ dysfunction contributes to a high mortality and poor prognosis, with a median survival time of 1-2 years from diagnosis. Here, we present a 46-yearold man with an exceptional clinical course of an LC multiple myeloma with generalized amyloidosis, causing renal insufficiency, congestive heart failure, and complete intestinal necrosis. We have summarized recent knowledge on AL amyloidosis, its association with monoclonal gammopathies, clinical presentations, diagnostic tools, and treatment strategies. Our comprehensive overview of this rare and often fatal disease aims to increase the awareness of AL amyloidosis. This may facilitate earlier diagnosis, and thus allow initiation of prompt and specific therapies, which are indispensable in order to improve disease prognosis. The Oncologist 2006;11:824-830

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“…The molecular mass of the Bence Jones protein varies from low molecular mass fragments to 22-kDa monomers or 44-kDa dimers (20). It has been documented that the Bence Jones proteins or light chain immunoglobulins form amyloid structures, which can be stained with Congo red (21). Polymerization of such proteins into amyloid might explain the apparent protease-resistance of these urinary proteins.…”

Section: ϫ06mentioning

confidence: 99%