Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• Oncogenic Ras mutations are prevalent in human cancers and represent critical therapeutic targets.
• Directly inhibiting Ras proteins with small molecules has proven exceptionally difficult due to their intracellular localization and function.
• Targeting intracellular proteins with antibodies presents a significant challenge in current antibody-based therapeutic strategies.

Purpose of the Study:

• To develop a novel therapeutic antibody capable of targeting and inhibiting oncogenic Ras mutants.
• To investigate the intracellular internalization and selective binding of the antibody to activated Ras.
• To evaluate the anti-tumor efficacy of the antibody in preclinical cancer models.

Main Methods:

• Development of a human IgG1 antibody (RT11) engineered for cytosolic internalization.
• Assessment of RT11's selective binding to GTP-bound oncogenic Ras mutants.
• Evaluation of RT11's ability to block Ras-effector protein interactions and downstream signaling.
• Testing of a tumor-targeting variant of RT11 in xenograft mouse models harboring oncogenic Ras mutations.

Main Results:

• RT11 successfully internalizes into living cells and selectively binds to activated oncogenic Ras mutants.
• The antibody effectively suppresses downstream signaling pathways and exhibits anti-proliferative effects on Ras-mutated tumor cells.
• A systemically administered RT11 variant with tumor-targeting capabilities significantly inhibited the growth of Ras-mutated tumor xenografts in vivo.
• Tumor xenografts with wild-type Ras were not affected by the RT11 variant, demonstrating specificity.

Conclusions:

• The development of RT11 demonstrates the feasibility of creating therapeutic antibodies targeting intracellular proteins like oncogenic Ras.
• This novel antibody approach offers a promising new avenue for treating cancers driven by Ras mutations.
• The findings pave the way for developing antibody-based therapies against previously inaccessible intracellular cancer targets.