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Antibody engineering to develop new antirheumatic therapies.

Isaacs JD - Arthritis Res. Ther. (2009)

Bottom Line: There is even a prevailing sense that disease 'cure' may be a realistic goal in the future.These developments were underpinned by an earlier revolution in molecular biology and protein engineering as well as key advances in our understanding of rheumatoid arthritis pathogenesis.This review will focus on antibody engineering as the key driver behind our current and developing range of antirheumatic treatments.

View Article: PubMed Central - HTML - PubMed

Affiliation: Wilson Horne Immunotherapy Centre and Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle-Upon-Tyne NE2 4HH, UK. j.d.isaacs@ncl.ac.uk

ABSTRACT
There has been a therapeutic revolution in rheumatology over the past 15 years, characterised by a move away from oral immuno-suppressive drugs toward parenteral targeted biological therapies. The potency and relative safety of the newer agents has facilitated a more aggressive approach to treatment, with many more patients achieving disease remission. There is even a prevailing sense that disease 'cure' may be a realistic goal in the future. These developments were underpinned by an earlier revolution in molecular biology and protein engineering as well as key advances in our understanding of rheumatoid arthritis pathogenesis. This review will focus on antibody engineering as the key driver behind our current and developing range of antirheumatic treatments.

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Antibody heavy-chain gene rearrangement, transcription, and translation. In step 1, any V segment (in this case, V2) rearranges to any D segment (in this case, D1). In step 2, the VD segment rearranges to one of the six J segments (in this case, J5). Primary RNA transcripts extend from the rearranged VDJ segments through to the Cδ gene (step 3). Finally, RNA processing results in the incorporation of either Cμ or Cδ by the transcripts, encoding for an IgM or IgD antibody, respectively.
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Figure 3: Antibody heavy-chain gene rearrangement, transcription, and translation. In step 1, any V segment (in this case, V2) rearranges to any D segment (in this case, D1). In step 2, the VD segment rearranges to one of the six J segments (in this case, J5). Primary RNA transcripts extend from the rearranged VDJ segments through to the Cδ gene (step 3). Finally, RNA processing results in the incorporation of either Cμ or Cδ by the transcripts, encoding for an IgM or IgD antibody, respectively.

Mentions: In humans, there are about 51 heavy-chain V segments, 25 D segments, and 6 J segments [6]. During B-cell development, antibody-encoding DNA undergoes various rearrangements (Figure 3). Essentially, any V segment can fuse to any D segment and any fused VD segment to any J segment. A similar process occurs in the light chain, where overall there are 71 V segment and 9 J segment (but no D segment) genes. This random pairing of segments (VDJ recombination) leads to a very large number of possible CDR3 sequences, explaining why CDR3 is the most variable CDR. In contrast, the sequences of CDR1 and CDR2 are encoded within the non-rearranged germline antibody sequence. The joins of V to D and D to J are imprecise, with loss or addition of nucleotides contributing to further CDR3 diversity. Further along the chromosome from the J segments are the C-region genes in the order Cμ (encodes IgM heavy chain), Cδ (encodes IgD heavy chain), and then the genes for the subclasses of IgG and IgA and for IgE. Following VDJ recombination, IgM or IgD antibodies are produced initially, dependent upon RNA-processing events (Figure 3).


Antibody engineering to develop new antirheumatic therapies.

Isaacs JD - Arthritis Res. Ther. (2009)

Antibody heavy-chain gene rearrangement, transcription, and translation. In step 1, any V segment (in this case, V2) rearranges to any D segment (in this case, D1). In step 2, the VD segment rearranges to one of the six J segments (in this case, J5). Primary RNA transcripts extend from the rearranged VDJ segments through to the Cδ gene (step 3). Finally, RNA processing results in the incorporation of either Cμ or Cδ by the transcripts, encoding for an IgM or IgD antibody, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2714093&req=5

Figure 3: Antibody heavy-chain gene rearrangement, transcription, and translation. In step 1, any V segment (in this case, V2) rearranges to any D segment (in this case, D1). In step 2, the VD segment rearranges to one of the six J segments (in this case, J5). Primary RNA transcripts extend from the rearranged VDJ segments through to the Cδ gene (step 3). Finally, RNA processing results in the incorporation of either Cμ or Cδ by the transcripts, encoding for an IgM or IgD antibody, respectively.
Mentions: In humans, there are about 51 heavy-chain V segments, 25 D segments, and 6 J segments [6]. During B-cell development, antibody-encoding DNA undergoes various rearrangements (Figure 3). Essentially, any V segment can fuse to any D segment and any fused VD segment to any J segment. A similar process occurs in the light chain, where overall there are 71 V segment and 9 J segment (but no D segment) genes. This random pairing of segments (VDJ recombination) leads to a very large number of possible CDR3 sequences, explaining why CDR3 is the most variable CDR. In contrast, the sequences of CDR1 and CDR2 are encoded within the non-rearranged germline antibody sequence. The joins of V to D and D to J are imprecise, with loss or addition of nucleotides contributing to further CDR3 diversity. Further along the chromosome from the J segments are the C-region genes in the order Cμ (encodes IgM heavy chain), Cδ (encodes IgD heavy chain), and then the genes for the subclasses of IgG and IgA and for IgE. Following VDJ recombination, IgM or IgD antibodies are produced initially, dependent upon RNA-processing events (Figure 3).

Bottom Line: There is even a prevailing sense that disease 'cure' may be a realistic goal in the future.These developments were underpinned by an earlier revolution in molecular biology and protein engineering as well as key advances in our understanding of rheumatoid arthritis pathogenesis.This review will focus on antibody engineering as the key driver behind our current and developing range of antirheumatic treatments.

View Article: PubMed Central - HTML - PubMed

Affiliation: Wilson Horne Immunotherapy Centre and Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle-Upon-Tyne NE2 4HH, UK. j.d.isaacs@ncl.ac.uk

ABSTRACT
There has been a therapeutic revolution in rheumatology over the past 15 years, characterised by a move away from oral immuno-suppressive drugs toward parenteral targeted biological therapies. The potency and relative safety of the newer agents has facilitated a more aggressive approach to treatment, with many more patients achieving disease remission. There is even a prevailing sense that disease 'cure' may be a realistic goal in the future. These developments were underpinned by an earlier revolution in molecular biology and protein engineering as well as key advances in our understanding of rheumatoid arthritis pathogenesis. This review will focus on antibody engineering as the key driver behind our current and developing range of antirheumatic treatments.

Show MeSH
Related in: MedlinePlus