Targeting CCRL2 enhances therapeutic outcomes in a tuberculosis mouse model

Area of Science:

• Immunology
• Infectious Diseases
• Pharmacology

Background:

• Tuberculosis (TB) is a leading cause of death, with limited new antimicrobial drugs.
• Host-directed therapies are being explored to improve TB treatment outcomes.
• C-C motif chemokine-like receptor 2 (CCRL2) is involved in leukocyte migration but its role in TB is unclear.

Purpose of the Study:

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

Main Methods:

• Assessed CCRL2 expression in macrophages, alveolar macrophages (AMs), dendritic cells (DCs), and neutrophils during Mtb infection in vitro and in vivo.
• Developed an anti-CCRL2 ADC using the cytotoxic drug SG3249.
• Evaluated the adjunctive therapeutic efficacy of the anti-CCRL2 ADC combined with the standard first-line TB regimen (RHZE) in Mtb-infected mice.

Main Results:

• Mtb infection increased CCRL2 expression in various immune cells in the lungs.
• Anti-CCRL2 ADC treatment potentiated RHZE efficacy, reducing lung inflammation.
• CCRL2 expression decreased in lung DCs and AMs with combined treatment.
• Neutrophils were eliminated, and IFN-γ/IL-17α T-cell responses were elevated in the anti-CCRL2 ADC + RHZE group.

Conclusions:

• CCRL2 targeting may enhance TB treatment outcomes.
• The anti-CCRL2 ADC potentially improves TB therapy by selectively eliminating infected innate immune cells.
• This approach offers a novel strategy for adjunctive TB treatment.