CD200R Immune Checkpoint Molecule for Drug Development

Overview of CD200R

CD200R is a suppressive receptor that engages with CD200, collectively governing the activity of myeloid cells. This interplay presents potential therapeutic implications for addressing hyperactive inflammation and leukemia. Furthermore, CD200R has homologous counterparts that impart activating cues, thus constituting a "complementary receptor" framework.

CD200R comprises characteristic immunoglobulin-like domains, encompassing an amino-terminal V-like domain followed by a smaller C2-like domain. In both molecules, the A-strand of the V-like domain aligns with the extensive GFCC'C" facet, as conventionally observed in immunoglobulin-like domains, while an abbreviated alpha helix is present within the EF loop of the V-like domain. The structural arrangement of the CD200/CD200R complex showcases nearly perpendicular interaction between the V-like domains of each molecule. This interaction involves the CD200 FCC'C" face along with the CC' and FG loops, which form a concave surface enveloping the relatively level AGFCC'C" face and FG loop of CD200R.

Fig. 1 The structure of CD200/CD200R complex molecular.¹

CD200R Involvement in Signal Pathways as an Immune Checkpoint

CD200R/CD200 signaling network engages various immune cell types, including T Cells, B Cells, and monocytes. CD200R initiates Dok2 activation, along with RasGAP/p120 engagement, culminating in the modulation of MAPK expression, restraint of Ras protein activation, and attenuation of PI3K and Erk bioactivity. Additionally, CD200-CD200R binding triggers a signaling cascade involving SHIP and RasGAP recruitment. Dok1 governs Dok2 activity, triggered by binding to specific phosphotyrosine residues within the CD200R cytoplasmic domain. Moreover, a succession of anti-inflammatory cues can be activated to suppress NF-kB. The amalgamation of Dok1 and CrkL, while inhibiting RasGAP activation, paradoxically leads to NF-κB activation and the induction of diverse pro-inflammatory profiles.

Fig. 2 The intricacies of CD200-CD200R signaling pathways.²

Case Study

Diverse mechanisms contribute to CD200/CD200R pro-tumorigenic function. (Shao, et al., 2023)

Fig. 3 Diverse mechanisms contribute to CD200/CD200R pro-tumorigenic function.³
The role of the CD200-CD200R axis in regulating an immunosuppressive tumor microenvironment highlights CD200 as a potential immune checkpoint target. CD200-activated myeloid-derived suppressor cells and tumor-associated macrophages directly suppress CD200R+ Th1 anti-tumor responses and activate tumor-infiltrating myeloid cells via CD200R signaling.

Engaging CD200R improves human ILC2-driven AHR. (Shafiei-Jahani, et al., 2021)

Fig. 4 Engaging CD200R improves human ILC2-driven AHR.⁴
In a humanized IL-33 mouse model, Agonistic treatment targeting anti-CD200R effectively mitigates human ILC2-induced airway hyperresponsiveness (AHR). Moreover, CD200R interaction suppresses both conventional and alternative NF-κB signaling pathways within activated ILC2s. Additionally, this study showcases both preemptive and remedial strategies employing CD200R engagement on ILC2s, resulting in enhanced airway resistance, dynamic compliance, and reduced eosinophilia.

Services at Creative Biolabs

Creative Biolabs emerges as a proficient enabler in the arena of immune checkpoint drug advancement, providing several services: immune checkpoint assays, biomarker development for immune checkpoint inhibitor (ICI), preclinical research for immune checkpoint targeting drugs, etc.

An extensive array of innovative agents aimed at the CD200/CD200R signaling pathways, including antibodies and small-molecule compounds, have been formulated and subjected to rigorous assessment across expansive pre-clinical trials. In response to the demanding criteria, Creative Biolabs has assembled a cadre of proficient researchers alongside purpose-built facilities and methodologies to deliver optimal drug discovery outcomes. Our tactics and procedures are adaptable to cater to the unique demands of any immune checkpoint molecule initiative. We encourage our customers to contact us for comprehensive insights.

References

Hatherley, Deborah, et al. "Structures of CD200/CD200 receptor family and implications for topology, regulation, and evolution." Structure 21.5 (2013): 820-832.
Ngwa, et al. "CD200-CD200R signaling and diseases: a potential therapeutic target?." International Journal of Physiology, Pathophysiology and Pharmacology 11.6 (2019): 297.
Shao, et al. "The immunoregulatory protein CD200 as a potentially lucrative yet elusive target for cancer therapy." Oncotarget 14 (2023): 96.
Shafiei-Jahani, Pedram, et al. "CD200–CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma." Nature communications 12.1 (2021): 2526.

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