C1QA

Complement C1q A chain (C1QA) is a subunit of C1q, the first component of the classical complement pathway, which is critical for the immune system's ability to recognize and clear pathogens, apoptotic cells, and immune complexes. C1q is a hexameric molecule consisting of three chains: A, B, and C, each encoded by a different gene. The A chain, encoded by the C1QA gene, plays a critical role in assembling the C1q complex and facilitating its biological functions. Structurally, C1q interacts with antibodies (IgG or IgM) bound to antigens, triggering a cascade of complement activation that leads to immune responses, including opsonization, inflammation, and cell lysis.

C1QA is primarily expressed in immune cells, such as macrophages and dendritic cells. Beyond its classical immune functions, emerging evidence highlights its roles in tissue repair, apoptosis, and the regulation of inflammation, making it a key player in immune homeostasis.

NCBI Gene ID: 712

UniProtKB ID: P02745

C1QA as a Drug Target

C1QA and the classical complement pathway are involved in maintaining immune homeostasis. However, dysregulation of C1QA activity can shift the balance between protection and inflammation, leading to pathological conditions. C1QA's ability to mediate both beneficial and harmful immune responses makes it an attractive therapeutic target, particularly for diseases in which complement overactivation or dysregulation plays a central role. Below are key areas where targeting C1QA may have therapeutic benefits:

• Autoimmune Diseases: Overactivation of the classical complement pathway is a hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In SLE, immune complexes containing autoantibodies activate C1q, leading to tissue damage through complement-mediated inflammation. In RA, the complement system contributes to joint inflammation and cartilage destruction. By inhibiting C1QA, therapies could attenuate excessive complement activation, reduce inflammation and preserve tissue integrity without compromising the immune system's ability to effectively eliminate pathogens.
• Neurodegenerative Disorders: In Alzheimer's disease and other neurodegenerative disorders, C1q binds to synapses and marks them for elimination by microglia. While synaptic pruning is essential during development, excessive C1q activity in aging or disease leads to the loss of functional synapses, contributing to cognitive decline. In addition, C1q-induced inflammation exacerbates neuronal damage. Modulating C1QA function, either by reducing its production or blocking its interactions with target synapses, could protect neuronal connections and slow disease progression.
• Cancer: C1QA has a dual role in cancer, depending on the tumor type and microenvironment. On one hand, it supports anti-tumor immunity by enhancing immune cell recruitment and complement-mediated lysis of cancer cells. On the other hand, excessive complement activation can promote chronic inflammation and tumor growth. C1QA's role in facilitating the remodeling of the tumor microenvironment adds complexity to its therapeutic targeting. Precise modulation of C1QA activity could enhance anti-cancer immune responses while reducing its tumor-promoting effects.
• Ischemia-Reperfusion Injury: Ischemia-reperfusion injury occurs when blood flow is restored to tissues after a period of oxygen deprivation, such as in myocardial infarction or stroke. This process triggers excessive complement activation, in which C1q plays a central role, causing secondary damage to cells and tissues. By targeting C1QA, therapies could reduce the inflammatory response and improve outcomes in patients recovering from ischemic events.

Figure 1. a C1q activates the classical complement pathway and induces phagocytosis, allowing apoptotic debris clearance. C1q also maintains quiescence by inhibiting antigen-presenting DC differentiation, which induces adaptive immunity. In the presence of DAMPs or PAMPs, such as HMGB1, C1q not only inhibits proinflammatory cytokine production but also promotes anti-inflammatory (M2) macrophage polarization that is critical for the resolution of inflammation. Once SLE develops, C1q suppresses DNA-containing immune complex (IC)-mediated pDC activation. b In contrast, in neuroinflammation or tumors, C1q promotes disease progression. In amyloid β plaques in AD or neuroinflammation, C1q promotes A1 astrocytes and activates microglia that degrade neurons. C1q and HMGB1 promote the loss of dendritic complexity and cognitive impairment. C1q inhibits CD8 + T cells and DCs that kill tumor cells. (Son, 2022)

Therapeutic Approaches Targeting C1QA

Inhibitors of C1q

Direct inhibitors of C1q, such as monoclonal antibodies or small-molecule inhibitors, are being explored to block complement activation at the initial stage of the classical pathway. These therapies may prevent C1 complex formation and downstream inflammatory effects while preserving other complement pathways, such as the alternative and lectin pathways, which are essential for innate immunity.

Modulators of C1q Expression

Therapies aimed at reducing C1QA gene expression may provide a systemic approach to limiting C1q production in diseases where it is overexpressed. This can be achieved through techniques such as RNA interference (RNAi) or antisense oligonucleotides. Such approaches may offer long-term benefits in chronic diseases such as SLE, where persistent overactivation of C1q contributes to disease progression.

Blocking Interactions

C1q exerts its function by binding to targets such as immunoglobulin complexes, apoptotic cells, or damaged tissues. Therapeutics that disrupt these interactions can provide selective modulation of C1q activity without affecting its synthesis or other immune functions. For example, peptides or small molecules that inhibit the binding of C1q to IgG/IgM could effectively prevent excessive complement activation in autoimmune diseases or ischemia-reperfusion injuries.

Drugs Targeting C1QA: Etanercept

• Type: Fusion protein (TNF inhibitor)
• Structure: A dimeric fusion protein consisting of two extracellular domains of the human TNF receptor (TNFR2, p75) linked to the Fc region of human IgG1.
• Mechanism of Action: Etanercept, which is primarily designed to bind and neutralize TNF-α, may also have indirect effects on complement activation. By reducing TNF-mediated inflammation, it may influence the expression of complement proteins, including C1q components. In addition, TNF signaling plays a critical role in regulating macrophage activity, which in turn affects modulation of the complement system.
• Clinical Applications: Etanercept is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. It has indirect effects on autoimmune diseases in which complement activation contributes to the pathology.

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References

1. Bulla R, Tripodo C, Rami D, et al. C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. Nat Commun. 2016;7(1):10346.
2. Sandev A, Singh S, Cracchiolo I, et al. The immune checkpoint controller C1q (C1qa/b/c) is a druggable oncologically relevant target: Proof-of-concept in vitro with an FDA-approved medicine, used as pioneer inhibitor of protein hydroxylation (273). Gynecologic Oncology. 2022;166:S145-S146.
3. Son M. Understanding the contextual functions of C1q and LAIR-1 and their applications. Exp Mol Med. 2022;54(5):567-572. doi:10.1038/s12276-022-00774-4
4. Yang H, Che D, Gu Y, Cao D. Prognostic and immune-related value of complement C1Q (C1qa, c1qb, and c1qc) in skin cutaneous melanoma. Front Genet. 2022;13:940306.