Development and characterization of human monoclonal antibodies that neutralize multiple TGFβ isoforms

Area of Science:

• Immunology
• Molecular Biology
• Drug Discovery

Background:

• Transforming growth factor-beta (TGFβ) isoforms are implicated in the progression of diseases including metastatic cancer and fibrosis.
• Targeting multiple TGFβ isoforms may be necessary for maximal therapeutic effect.
• Existing therapies may not address the full spectrum of TGFβ isoform involvement in disease.

Purpose of the Study:

• To discover and develop potent, pan-isoform neutralizing antibodies against TGFβ.
• To identify an antibody capable of inhibiting TGFβ1, TGFβ2, and TGFβ3.
• To evaluate the therapeutic potential of a high-affinity, affinity-matured TGFβ-neutralizing antibody.

Main Methods:

• Utilized fully human antibody phage display libraries for antibody discovery.
• Employed affinity maturation techniques, including light chain shuffling, to enhance antibody potency.
• Assessed antibody binding, neutralization capacity in vitro (cell proliferation, cytokine release, SMAD2 phosphorylation), and in vivo efficacy (xenograft tumor burden).

Main Results:

• Initial screening identified antibodies with varying isoform specificities; none were uniformly potent pan-isoform neutralizers.
• Affinity maturation yielded a high-affinity antibody clone that potently neutralizes all three major TGFβ isoforms.
• The affinity-matured antibody demonstrated superior efficacy in reducing tumor burden in a xenograft model compared to its parent clone.
• In vitro assays confirmed potent inhibition of TGFβ signaling pathways.

Conclusions:

• A novel, high-affinity antibody effectively neutralizes all three main TGFβ isoforms.
• This pan-isoform neutralizing antibody exhibits significant therapeutic potential for diseases driven by TGFβ.
• The developed antibody represents a promising candidate for therapeutic intervention in human diseases associated with TGFβ dysregulation.