Targeting CCRL2 enhances therapeutic outcomes in a tuberculosis mouse model

Area of Science:

• Immunology
• Infectious Diseases
• Pharmacology

Background:

• Tuberculosis (TB) is a leading infectious cause of death globally.
• Limited antimicrobials necessitate host-directed therapies for improved TB treatment.
• The role of C-C motif chemokine-like receptor 2 (CCRL2) in TB infection is largely unknown.

Purpose of the Study:

• To investigate the role of CCRL2 in Mycobacterium tuberculosis (Mtb) infection.
• To develop and evaluate a novel anti-CCRL2 antibody-drug conjugate (ADC) as an adjunctive TB therapy.

Main Methods:

• Mtb infection model in mice to assess CCRL2 expression in macrophages and lungs.
• Development of an anti-CCRL2 ADC using the cytotoxic drug SG3249.
• Testing adjunctive efficacy of anti-CCRL2 ADC combined with the standard RHZE regimen.

Main Results:

• Mtb infection upregulated CCRL2 expression in mouse macrophages and lungs.
• Anti-CCRL2 ADC treatment potentiated RHZE efficacy, reducing lung inflammation.
• Treatment decreased CCRL2 expression in specific immune cells and eliminated neutrophils, while enhancing beneficial T-cell responses.

Conclusions:

• CCRL2-targeting approaches show promise for improving TB treatment outcomes.
• Selective targeting of Mtb-infected innate immune cells may be a mechanism for improved efficacy.
• Host-directed therapy with anti-CCRL2 ADC offers a potential adjunctive strategy for TB control.