The biopharmaceutical industry confronts a significant and costly obstacle in the form of a high drug candidate failure rate during clinical trials. A substantial majority, approximately 90%, of all drug candidates that enter clinical trials do not succeed, with a significant proportion of these failures—60% due to a lack of efficacy and 30% due to unmanageable toxicity—stemming from a fundamental lack of predictability in preclinical models. This systemic issue contributes to the exorbitant cost and protracted timeline of drug development, which can exceed a decade and cost upwards of $1 billion for a single therapeutic to reach the market. The primary source of this problem lies in the inherent biological discrepancies between traditional preclinical animal models and human physiology, which lead to unreliable data that poorly predict human outcomes.
But in the fast-evolving field of complement biology, a new paradigm is emerging. This shift is not just about finding new targets; it's about pioneering new therapeutic modalities and, crucially, developing the advanced preclinical models required to test them.
| Drug Name | Target | Modality | Clinical Indication(s) | Status | Key Feature |
|---|---|---|---|---|---|
| Pegcetacoplan | C3 | Synthetic Cyclic Peptide | PNH, GA, C3G | FDA Approved (PNH, GA) | First FDA-approved C3 inhibitor |
| Zilucoplan | C5 | Synthetic Macrocyclic Peptide | gMG | FDA Approved | First once-daily subcutaneous C5 inhibitor |
| Ravulizumab | C5 | Monoclonal Antibody (mAb) | PNH, aHUS | FDA Approved | Long-acting (administered every 8 weeks) |
| Pozelimab | C5 | Monoclonal Antibody (mAb) | CHAPLE Disease | FDA Approved | First and only treatment for CHAPLE |
| Cemdisiran | C5 | siRNA | IgA Nephropathy | Phase III | RNAi therapeutic |
| Dual C3/C5 Inhibitor | C3，C5 | Bispecific Antibody | C3G, AMD | Phase III | Dual-target approach |
The therapeutic potential of the complement system—a cornerstone of the innate immune system—was first brought to the forefront by the success of C5 inhibitors . Eculizumab, the first C5 inhibitor, achieved blockbuster status and led to AstraZeneca’s acquisition of Alexion in a $39 billion deal . Its long-acting successor, Ravulizumab, has also seen rapid commercial adoption.
Despite this success, a significant clinical limitation surfaced: while C5 inhibitors effectively stop intravascular hemolysis, they fail to prevent C3-mediated extravascular hemolysis, leaving patients with persistent anemia .
This unmet need drove a strategic pivot. The development of Pegcetacoplan, the world’s first targeted C3 inhibitor, proved the value of an upstream approach . By blocking the complement cascade at the level of C3, this therapy addresses both intravascular and extravascular hemolysis . A head-to-head Phase III trial compellingly demonstrated its clinical superiority over Eculizumab, with significant improvements in hemoglobin levels and a reduction in transfusion requirements . This pivot validated C3 as a druggable target and paved the way for even more innovative approaches.
The field is now moving beyond traditional monoclonal antibodies to a new generation of therapeutic modalities that promise greater precision and durability.
- SiRNA-Based Therapeutics: Small interfering RNA (siRNA) represents a paradigm shift by targeting the root cause of protein over-expression at the genetic level. A single dose of an siRNA therapeutic can lead to a prolonged reduction in the target protein, significantly reducing administration frequency and improving patient convenience. RNAi therapies like Cemdisiran are already in late-stage clinical trials for conditions like IgA nephropathy.
- Bispecific Antibodies: Bispecific antibodies (bsAbs) are engineered with two distinct binding sites, enabling them to engage two different antigens simultaneously. This dual-targeting capability allows for a sophisticated approach, such as designing a bsAb to recruit the body's own complement regulatory proteins to a specific site of pathology, thereby achieving localized inhibition without compromising systemic immunity.
The development of these highly specific, human-centric drugs has exposed a critical gap in the preclinical research paradigm.
- Species-Specific Interactions: Modern biologics are designed to interact with human proteins. Consequently, data from conventional mouse models—which express murine orthologs—are often unreliable and may fail to accurately predict therapeutic outcomes in humans. For example, the neonatal Fc receptor (FcRn), which plays a key role in antibody clearance, has species-specific binding differences that make PK/PD studies in wild-type mice unreliable for predicting human PK profiles.
- Disease Pathophysiology: Fundamental differences in physiology and disease progression between mice and humans can render mouse models poor predictors of drug efficacy and safety .
The very feature that makes these advanced therapeutics so promising—their high specificity for human targets—simultaneously makes them impossible to test in traditional animal models.
Cyagen's C3 and C5 humanized mouse models are a direct response to this translational challenge. Built on the proprietary HUGO-GT™ platform, these models are created through a precise gene replacement technology that seamlessly integrates the full human C3 and C5 genes into the mouse genome, preserving endogenous spatial and temporal expression patterns.
| Product Name | Product NO. | Strain Name | Type |
|---|---|---|---|
| B6-hC3 | I001135 | C57BL/6JCya-C3tm1(hC3)/Cya | C3 Humanized |
| B6-hC5 | C001824 | C57BL/6JCya-Hctm1(hC5)/Cya | C5 Humanized |
The meticulous validation of these models provides a high degree of confidence for researchers.
- Protein and Gene Expression: ELISA and RT-qPCR analysis confirm the robust expression of human C3, C5, and C5a proteins in the serum of the humanized mice, with a complete absence of the endogenous murine genes.
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Phenotypic Validation: The C3 humanized model's retinal health and function were validated using advanced techniques like Fundus, OCT, and ERG, demonstrating that the human gene replacement does not compromise the model’s physiological baseline.
Figure 4: Fundus and OCT images comparing the retinal morphology of B6-hC3 and wild-type mice.
Figure 5: A graph of ocular ERG results showing similar a- and b-wave amplitudes in B6-hC3 and wild-type mice. -
C5 Model Specifics: The validation data for the B6-hC5 model revealed that it also expresses the human C5 gene in tissues like the liver and lungs, and human C5 and C5a proteins in serum.
Figure 6: A graph showing the gene expression of human C5 and mouse C5 in the liver and lungs of B6-hC5 and wild-type mice.
Figure 7: A graph showing the protein expression of human C5 and C5a in the serum and plasma of B6-hC5 and wild-type mice.
The next era of complement therapeutics—defined by the durable, gene-silencing power of siRNAs and the localized precision of bispecific antibodies—can only be realized through the use of clinically relevant preclinical platforms.
Cyagen's C3 and C5 humanized mouse models are not just research tools; they are foundational technologies that bridge the translational gap and accelerate the path from discovery to clinical application. By providing a reliable system that truly mirrors human biology, they are actively shaping the future of precision medicine in immunobiology.
- Coulthard LG, Hawksworth OA, Woodruff TM. Complement: The Emerging Architect of the Developing Brain. Trends Neurosci. 2018 Jun;41(6):373-384. doi: 10.1016/j.tins.2018.03.009. Epub 2018 Mar 29. PMID: 29606485.
- Conversano E, Vivarelli M. Advances in Complement Inhibitory Strategies for the Treatment of Glomerular Disease: A Rapidly Evolving Field. J Clin Med. 2025 Jun 13;14(12):4204. doi: 10.3390/jcm14124204. PMID: 40565949; PMCID: PMC12194467.
- Kriya Therapeutics. Ophthalmology Pipeline. Available at: https://kriyatherapeutics.com/pipeline/ophthalmology/. Accessed July 3, 2025.
