Abagovomab is a mouse anti-idiotypemonoclonal antibody whose variable epitope mimics the tumour-associated antigen CA-125, which is highly expressed in epithelialovarian cancer. Unlike antibodies that directly target CA-125, abagovomab acts as a "surrogate" antigen. By mimicking CA-125, it prompts the immune system to recognize and attack tumour cells expressing this protein. It is hoped that this immune response will eliminate residual tumour cells and help prevent disease recurrence.[medical citation needed][1]
Mechanism of action
Abagovomab was engineered to mimic the tumor-associated antigen CA-125, which is highly expressed in over 80% of epithelial ovarian cancers. It was generated by immunizing mice with the OC125 antibody, leading to the production of anti-idiotypic antibodies (Ab2) that structurally resemble CA-125. Administration of abagovomab stimulates the patient’s immune system to produce anti-anti-idiotypic antibodies (Ab3), which can recognize and potentially target CA-125-expressing tumor cells[3][8] (PMID 21241213, PMC5795662).[2][3]
Development
Preclinical and early clinical studies
Preclinical studies confirmed that abagovomab induced both humoral and cellular immune responses against CA-125. Early phase I and Ib/II clinical studies primarily assessed safety and immunogenicity, demonstrating that abagovomab was well tolerated, with most adverse events being mild and self-limited, such as local injection site reactions and mild systemic symptoms. A strong Ab3 antibody response was observed in a significant proportion of patients, and this response was associated with prolonged overall survival.[1][4]
Subsequent phase I trials explored different doses and routes of administration (intramuscular vs. subcutaneous) to optimize immunogenicity and safety. Both routes and doses were safe, and robust Ab3 responses were observed across all groups. The subcutaneous route was ultimately favored for ease of administration.[4]
Phase III trials
Encouraged by early data, the pivotal phase III MIMOSA (Monoclonal antibody Immunotherapy for Malignancies of Ovary by Subcutaneous Abagovomab) trial was launched. This large, double-blind, placebo-controlled study enrolled patients with epithelial ovarian cancer who had achieved complete clinical remission after standard treatment, administering abagovomab subcutaneously in an induction and maintenance schedule for up to 21 months.[1] Despite the strong immunogenicity the MIMOSA trial failed to show a statistically significant improvement in recurrence-free or overall survival compared to placebo. The hazard ratios for recurrence-free and overall survival indicated no meaningful difference between the abagovomab and placebo groups. Consequently, the development of abagovomab for ovarian cancer was discontinued, and the phase III program was terminated in both the US and EU by 2015.[3][5]
Ovarian cancer is the most malignant tumour of the female reproductive organs. After endometrial cancer, it is the second most common genital tumour in women with c. 9,000 women newly affected each year and, because of its aggressiveness, it has the highest mortality rate. This is due in part to the fact that there is no screening examination for early detection, and that the disease is therefore usually only discovered at an advanced stage, and in part to the tumour's tendency, although responding well to initial treatment, to recur again later.[medical citation needed]
In spite of initially successful treatment with surgery and chemotherapy, which forces back the tumour "completely", i.e. into no longer visible residues, there is a relapse of the disease (recurrence) in more than half the women affected. Today, no further therapy would be conducted in this situation as long as the disease did not occur again, i.e. clinical monitoring of the symptom-free patients as part of follow-up care is the current standard procedure. In this time-window of the patient's history so called ‘watch and wait’ abagovomab is potentially capable of deferring or even preventing the occurrence of the relapse.[medical citation needed]
1 2 Sabbatini P, Dupont J, Aghajanian C, Derosa F, Poynor E, Anderson S, etal. (September 2006). "Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer". Clinical Cancer Research. 12 (18): 5503–5510. doi:10.1158/1078-0432.CCR-05-2670. PMID17000686. S2CID18208677.
↑ Battaglia A, Fossati M, Buzzonetti A, Scambia G, Fattorossi A (November 2017). "A robust immune system conditions the response to abagovomab (anti-idiotypic monoclonal antibody mimicking the CA125 protein) vaccination in ovarian cancer patients". Immunology Letters. 191: 35–39. doi:10.1016/j.imlet.2017.09.006. PMID28919454.
Further reading
Wagner U, Köhler S, Reinartz S, Giffels P, Huober J, Renke K, etal. (May 2001). "Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment. See The biology behind: Foon KA, Bhattacharya-Chatterjee M, Are solid tumor anti-idiotype vaccines ready for prime time? Clin. Cancer Res., 7:1112-1115, 2001". Clinical Cancer Research. 7 (5): 1154–1162. PMID11350879.
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