Complement-Based Strategy Against CRC

Activating Complement versus CRC

molecular-level therapeutic strategy to turn the complement system (C’) against colorectal cancer (CRC) cells so that the membrane attack complex (MAC, C5b–C9) lyses tumor cells. Here’s how that work:

🔬 Complement-Based Strategy Against CRC

1. The Problem

• CRC cells often evade complement attack by:

  • Overexpressing complement regulatory proteins (CRPs) such as CD46, CD55 (DAF), CD59 (Protectin).

    • CD55 prevents C3/C5 convertase formation.

    • CD59 blocks MAC insertion.

• Tumor microenvironment (TME) suppresses immune activation (Tregs, MDSCs, TGF-β, etc.).

Thus, complement is kept “off” on CRC cells, even when antibodies bind.

2. Therapeutic Strategy: Force MAC Formation

(a) Target CRC cells with antibodies that fix complement

• Use monoclonal antibodies (mAbs) against CRC tumor antigens (e.g. CEA, EpCAM, HER2, EGFR, PD-L1) designed for strong C1q binding.

• These activate the classical pathway → C3 convertase → C5 convertase → MAC.

(b) Block complement regulators on tumor cells

• Inhibit CD55/CD59 using:

  • Blocking antibodies

  • siRNA / ASOs against CD55/CD59

  • CRISPR-based knockdown in experimental models

• Without these, tumor cells lose their complement shield → MAC can assemble.

(c) Enhance complement amplification

• Deliver recombinant C3/C5 convertase stabilizers (e.g. properdin analogs).

• Use C5a receptor agonists to boost local complement activation (but balance against inflammation).

(d) Combination with Immunotherapy

• Checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4) unleash T cells → generate more antibodies → feed into complement activation.

• Oncolytic viruses engineered to express complement-activating Fc fragments could also seed tumor lesions with complement triggers.

3. Molecular Cascade

Step 1: Antibody binds CRC antigen (CEA, EpCAM, etc.)
Step 2: C1q recruited → Classical complement pathway → C3/C5 convertases
Step 3: Block CD55/CD59 → convertases remain active
Step 4: C5 → C5b, recruits C6–C9 → MAC pores form
Step 5: CRC cell lysis (osmotic shock)

4. Safety Considerations

• Risk: Excess complement = bystander damage to normal colon tissue.

• Solution:

  • Tumor-targeted antibody delivery (bispecific mAbs, nanocarriers).

  • Local complement boosting (intra-tumoral injection of C5 agonists).

  • Check dosing carefully to avoid systemic complement storm.

✅ Summary:To overcome CRC tumors via complement:

1. Use complement-fixing antibodies against tumor antigens.

2. Inhibit CD55/CD59 on CRC cells.

3. Boost complement amplification locally.

4. Combine with checkpoint blockade or oncolytic virotherapy for synergy.