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The effects of Antibody Engineering CH and CL in Trastuzumab and Pertuzumab recombinant models: Impact on antibody production and antigen-binding.

ABSTRACT: Current therapeutic antibodies such as Trastuzumab, are typically of the blood circulatory IgG1 class (C?/ CH?1). Due to the binding to Her2 also present on normal cell surfaces, side effects such as cardiac failure can sometimes be associated with such targeted therapy. Using antibody isotype swapping, it may be possible to reduce systemic circulation through increased tissue localization, thereby minimising unwanted side effects. However, the effects of such modifications have yet to be fully characterized, particularly with regards to their biophysical properties in antigen binding. To do this, we produced all light and heavy chain human isotypes/subtypes recombinant versions of Trastuzumab and Pertuzumab, and studied them with respect to recombinant production and Her2 binding. Our findings show that while the light chain constant region changes have no major effects on production or Her2 binding, some heavy chain isotypes, in particularly, IgM and IgD isotypes, can modulate antigen binding. This study thus provides the groundwork for such isotype modifications to be performed in the future to yield therapeutics of higher efficacy and efficiency.

SUBMITTER: Lua WH

PROVIDER: S-EPMC5768722 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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The effects of Antibody Engineering CH and CL in Trastuzumab and Pertuzumab recombinant models: Impact on antibody production and antigen-binding.

Lua Wai-Heng WH Ling Wei-Li WL Yeo Joshua Yi JY Poh Jun-Jie JJ Lane David Philip DP Gan Samuel Ken-En SK

Scientific reports 20180115 1

Current therapeutic antibodies such as Trastuzumab, are typically of the blood circulatory IgG1 class (Cκ/ CHγ1). Due to the binding to Her2 also present on normal cell surfaces, side effects such as cardiac failure can sometimes be associated with such targeted therapy. Using antibody isotype swapping, it may be possible to reduce systemic circulation through increased tissue localization, thereby minimising unwanted side effects. However, the effects of such modifications have yet to be fully ...[more]

PMID: 29335579

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Project description:BACKGROUND:NeoSphere showed significantly higher pathologic complete response (pCR) with neoadjuvant pertuzumab, trastuzumab, and docetaxel compared with trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. We assessed associations between human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers and clinical outcome in response to these regimens. METHODS:Tumor, serum, and whole blood samples were collected at baseline and post neoadjuvant treatment before surgery. Associations between biomarkers and pCR, and between biomarkers and clinical variables were assessed in the overall and estrogen receptor (ER)-positive and ER-negative populations. Changes in serum marker levels between baseline and post-neoadjuvant treatment were examined. RESULTS:No markers were associated with pCR across all groups; however, significant associations were observed for two markers in individual groups. High HER2 was significantly associated with higher pCR rates (P?=?0.001) and a significant treatment interaction (P?=?0.0236) with pertuzumab, trastuzumab, and docetaxel (odds ratio 2.07, P?=?0.01). Low serum transforming growth factor alpha (TGF?) was associated with higher pCR rates with pertuzumab plus trastuzumab (P?=?0.04) without a significant treatment interaction. Presence of truncated HER2 did not affect pCR. A non-significant decreased pCR benefit was observed consistently across groups in patients with mutated PIK3CA while the treatment benefit from pertuzumab was maintained when comparing the trastuzumab plus docetaxel and pertuzumab, trastuzumab, and docetaxel groups. Notably, PIK3CA exon 9 mutations were associated with residual disease (pooled groups), which was not found for exon 20 mutations. Serum HER2 extracellular domain levels were significantly increased between baseline and post-neoadjuvant treatment in the non-trastuzumab-treated group, and decreased in the trastuzumab-containing groups (likely due to trastuzumab's mechanism of action). Differences in biomarker profiles according to ER status were observed. CONCLUSIONS:The observed associations of HER2 protein levels with sensitivity to pertuzumab, and of PIK3CA exon 9 mutation to lack of sensitivity to HER2-targeted monoclonal antibody treatment, warrant further investigation. Previously reported findings of truncated forms of HER2 as resistance markers to HER2-targeted treatment could not be confirmed in NeoSphere. Conventional HER2 assessment should continue and HER2 remains the only biomarker suitable for patient selection in this population. TRIAL REGISTRATION:Clinicaltrials.gov, NCT00545688 . Registered on 16 October 2007.

Project description:Purpose of Review:The requirement for large quantities of therapeutic proteins has fueled a great interest in the production of recombinant proteins in plant bioreactors. The vaccines and bio-therapeutic protein production in plants hold the promise of significantly lowering the cost of manufacturing life-saving drugs. This review will reflect the current status and challenges that the molecular farming platform faces becoming a strategic solution for the development of low-cost bio-therapeutics for developing countries. Recent Findings:Different plant parts have been successfully identified as suitable expression systems for the commercial production of therapeutic proteins for some human and animal diseases ranging from common cold to AIDS. The processed therapeutics from such sources are devoid of any toxic components. The large-scale cultivation of these transgenic plants would be possible anywhere in the world including developing countries, which lack sophisticated drug manufacturing units. A couple of such commercially generated products have already hit the market with success. Newer methods using suitable plant viruses and recombinant gene expression systems have already been devised for producing therapeutic proteins and peptides. Summary:Plants are promising bio-factories for therapeutic protein production because of their several advantages over the other expression systems especially the advanced mechanisms for protein synthesis and post-translational modification which are very much similar to animal cells. Plant biotechnologists are much attracted to the bio-farming because of its flexibility, scalability, low manufacturing cost, as well as the lack of risk of toxic or pathogenic contamination. A number of projects on bio-farming are designed and are at various developmental stages but have not yet become available to the pharmaceutical industry. Therefore, we need further advancement in the optimization of lab protocols for up-scaling the production of such therapeutics at commercial level with a promise to offer their best clinical use.

Dataset Information

The effects of Antibody Engineering CH and CL in Trastuzumab and Pertuzumab recombinant models: Impact on antibody production and antigen-binding.

Publications

The effects of Antibody Engineering CH and CL in Trastuzumab and Pertuzumab recombinant models: Impact on antibody production and antigen-binding.

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