Anti-TGF-beta Antibody Hinge Mutation for Purity and Half-Life
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Solution Overview
Problem
There is a need for pan-specific therapeutic antibodies targeting human TGF-β that are safe and effective, as existing antibodies face challenges due to TGF-β's high conservation across species, leading to difficulties in production and limited treatment options for conditions like advanced melanoma, where current therapies like anti-PD1 antibody monotherapy show low response rates.
Innovation Solution
Development of monoclonal antibodies that specifically bind to human TGF-β1, TGF-β2, and TGF-β3 with a mutation at position 228, reducing half-antibody formation and enhancing pharmacokinetic profiles, allowing for improved clinical benefits and increased efficacy when used in combination with immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If traditional monoclonal antibodies are produced to target human TGF-β, then they can bind to TGF-β isoforms, but they form half-antibody dimers during manufacturing which reduces purity and efficacy
Solution Approach 1:
The patent applies parameter changes by mutating the hinge region amino acid sequence of the antibody constant region (specifically changing cysteine to serine at position 228 in EU numbering). This parameter change in the molecular structure prevents disulfide bond formation between heavy and light chains, thereby eliminating half-antibody dimer formation during manufacturing and improving antibody purity.
2Duration of action of moving object
If existing anti-TGF-β antibodies are used for treatment, then they can inhibit TGF-β signaling, but they have limited half-life and require frequent administration
Solution Approach 1:
The patent modifies the pharmacokinetic parameters of the antibody by introducing a mutation in the hinge region (cysteine to serine at position 228). This parameter change improves the antibody's stability and reduces clearance rates, thereby extending the half-life of the antibody in circulation and reducing the frequency of administration required.
3Adaptability or versatility
If pan-specific antibodies targeting all TGF-β isoforms are developed, then they can provide broad coverage, but TGF-β's high conservation across species makes production challenging
Solution Approach 1:
The patent applies local quality by designing the antibody variable regions to specifically recognize conserved epitopes on all three human TGF-β isoforms while maintaining human specificity. The local modification of the hinge region (cysteine to serine mutation) further enhances this by preventing cross-species binding and half-antibody formation, thereby achieving pan-specificity without compromising manufacturability.
4Reliability
If current immunotherapy monotherapies like anti-PD1 are used for advanced melanoma, then they can activate immune response, but more than 50% of patients do not achieve complete or partial response
Solution Approach 1:
The patent applies merging by combining anti-TGF-β antibody therapy with immune checkpoint inhibitors like anti-PD1. The anti-TGF-β component neutralizes the immunosuppressive microenvironment created by TGF-β, while the immune checkpoint inhibitor activates immune response. This combination therapy addresses both the suppression and activation aspects of immune response, thereby improving response rates in advanced melanoma patients who do not respond to monotherapy.
Data Source
AI summary
The invention provides an improved pan-TGF-β antibody for treatment of conditions that are mediated by TGF-β, including autoimmune diseases, fibrotic conditions, and cancers. Also provided are methods and uses of the antibody in conjunction with other immunomodulatory agents such as an anti-PD-1 antibody.