Oregovomab – OvaRex; Mab B43.13; CA125 tumor antigen monoclonal antibody
Status: U.S. development halted in Dec. 2007; marketed in UK., France and some other EU countries
Organizations involved:
ViRexx Medical Corp. – R&D; Tech.; Parent
AltaRex Medical Corp. – Former
Unither Pharmaceuticals, Inc. – USA mark.; Asia mark.; Germany mark.
United Therapeutics Corp. – Parent
Sigma-Tau Group – Manuf.; Europe mark.
Abbott Labs. – Former
Abbvie – Manuf.
Dompé Farmaceutici – Former
FAES Farma S.A. –Former
Genesis Pharma S.A. – Former
Medison Pharma Ltd. –Middle East mark
Cross ref: See the Monoclonal Antibodies entry (#300).
Description: OvaRex is a formulation of photoactivated oregovomab, a murine (mouse) B43.13 monoclonal antibody, an ultraviolet (UV) light (photo)activated antibody that binds specifically to ovarian cancer antigen CA 125 at the 43.13 epitope. The oregovomab dimer has a molecular weight of about 150 kDa.
Nomenclature: OvaRex [TR]; oregovomab [USAN INN]; immunoglobulin G1, anti-(human CA125 (carbohydrate antigen)) (mouse monoclonal B43.13gamma1-chain), disulfide with mouse monoclonal B43.13kappa-chain, dimer [CAS]; 213327-37-8 [CAS RN]; MAb B43.13 [SY]; B43.13 [SY]; MAb-B43.13 [SY]; ATCC PTA-1883 [ATCC]
Biological.: Oregovomab (and OvaRex) targets the 43.13 epitope of CA125, a specific ovarian tumor marker present in the circulation and on cancer cells that have escaped removal following primary surgical treatment of advanced ovarian cancer. CA125 and other specific antigens expressed almost exclusively on cancer cells (tumor associated antigens, or TAAs) are ideal targets for antibodies that act as immunotherapeutic agents. These tumor specific antigens are self-produced and are not typically recognized as harmful by the patients’ immune system. In some cases they actively inhibit immune responses. CA125 is over-expressed by the majority of late-stage ovarian cancer patients. CA125 has multiple epitopes recognized by different antibodies such as OC125, M11, B43.13, B27.1, among others. Oregovomab/OvaRex is designed to help patients fight their disease by stimulating a novel immune response to CA125.
Oregovomab binds to soluble CA125 tumor associated antigen. Binding of the antibody to the targeted epitope of the multi-epitopic CA125 tumor-associated antigen alters the antigen’s epitope structure so that the host immune system recognizes and initiates an immune response to the previously unrecognized antigens. The binding of the antibody to the CA125 antigen exposes epitopes of joined molecules, inducing humoral (antibody) responses to epitopes on both molecules. This includes a human anti-mouse antibody (HAMA) responses to the oregovomab murine antibody which has been shown to correlate with antitumor activity; and cellular immune responses, including cytotoxic T-cell responses to ovarian tumor tissue.
The binding of the antibody to CA125 antigen essentially reprograms the immune system to recognize the “self” CA125 antigen as “foreign”, thereby triggering the immune system to effectively respond to and attack the antigens and their associated tumors. Thus, the body’s immune system creates humoral (antibody) and cellular (T cell and B cell) responses against both the monoclonal antibody and the tumor specific antigen to which it binds. Unlike free CA 125, CA 125-oregovomab complexes can prime dendritic cells, leading to downstream activation of T-lymphocytes (T-cells). ViRexx claims it “is the only company pursuing this novel application of monoclonal antibodies for tumor specific antigens, to reprogram the human immune system to attack cancer cells.”
Oregovomab was originally developed as part of a radioimmune conjugate with technicium radioisotope for radiodiagnostic imaging of ovarian tumors. In the July 2001 issue of the American Journal of Obstetrics and Gynecology, it was reported that prolonged survival was an unexpected outcome when technicium-99m-labeled MAb-B43.13 was first administered as a diagnostic agent to women with recurrent ovarian cancer. Further study indicated that the monoclonal antibody alone was associated with anti-tumor activity.
With orgovomab, relatively small dosages, e.g., <2 mg, are effective to induce potent CA125 and oregovomab immune responses in humans. Various studies suggest a correlation exists between the extent of the immunogenic response against CA125 and progression-free and/or survival time of patients. Although , oregovomab is immunogenic, oregovomab/Ovarex has been shown to not induce toxicity traditionally associated with HAMA responses and murine antibody adminstration.
The network theory suggests that some of the secondary antibodies (Ab2) induced by oregovomab will have a binding site that is the complement of the complement of the original antigen, and thus will reproduce the “internal image” of the original antigen. In such an anti-idiotypic antibody response, antibodies to an antigen in turn induce antibodies that react with the original antigen, e.g., CA125.
Hybridoma cell line B43-13 expressing B43.13 antibody was deposited in the American Type Culture Collection (ATCC) patent repository as Patent Deposit Designation PTA-1883 (ATCC PTA-1883).
CA125 is present in over 90% of ovarian cancer patients. It is also present in substantial numbers of patients with other forms of cancers, including breast, lung, ovarian and pancreatic cancers, suggesting that Oregovomab/Ovarex has potential for treating other than ovarian cancer. As indicated by results from clinical studies, when an antibody (oregovomab) against a single epitope (B43.13) was injected into patient, an antibody response was induced against the whole antigen which recognizes different epitopes present in the antigen (CA125), indicating that the conformation and presentation of immunogenic CA125 epitopes have been altered in the antigen portion of the antibody-antigen complex. CA125 antibody alone causes tumor cell lysis through antibody dependent cellular cytotoxicity (ADCC). Although injected oregovomab does not cause by itself an ADCC and/or complement dependent cytolysis mediated lysis of ovarian tumor cells, the generation of CA125 antibodies in patients injected with oregovomab, leads to tumor cell lysis.
Oregovomab is “photoactivated” during its manufacture, involving exposure to ultraviolet (UV) light. It has long been known that exposure of antibodies to UV light changes the reactivity of antibodies toward the native/targeted protein. These changes are reflected in the structural components of the binding site between the protein and the antibody. Generally, in vivo immunological responses to UV-exposed proteins are reduced, due in part to the creation of new antigenic determinants. UV irradiation has also been used to modify proteins for conjugation purposes. UV light exposure enhances antibodies’ conjugation characteristics while reducing isotypic immunogenicity or immunogenicity to the constant (Fc) portion of the antibody.
Unexpectedly, AltaRex found that UV light can en-hance immunogenicity of whole antibodies, including increasing the recognition and/or response of an anti-idiotypic and/or anti-isotypic antibody. UV light exposure may not affect the antibody binding to antigen, as is the case with oregovomab, but rather rather affects the antibody’s ability to act as an immunogen. Administration of UV-exposed antibodies to a cancer patient may generate production of anti-idiotypic antibodies to the UV-exposed antibody, with these antibodies reacting with the original antigen. This response may provide a therapeutic advantage via the humoral and cellular consequences directed to the cancer cells. Thus, oregovomab induced anti-idiotypic antibodies and immune responses directed to CA125.
Photoactivation results in disulfide cleavage with sulfhydryl bond generation. The exact mechanism of activation is unknown. Perhaps the antibody hydrophobicity/hydrophilicity is altered by minor tryptophan disruption in combination with sulfhydryl generation to enhance its recognition/response by the immune cells. Or, the photoactivated antibody’s constant (Fc) portion has key amino acid specific changes which enhance Fc-mediated antigen presenting cell recognition. Binding of the photoactivated antibody to a pre-determined epitope of a multi-epitopic tumor-associated antigen alters the antigen so that the host immune system can recognize and initiate an immune response to this previously unrecognized antigen. This is not related to changes in the polymeric state of the antibody protein involving aggregated forms (as observed for human immunoglobulins after UV exposure), which are directed to phagocytic cells, since the photoactivated product maintains its monomeric state. The extent of presentation and responses to photoactivated antibody/antigen complex increase, as detected by the increased HAMA response of antigen-positive patients injected with the antibody.
In vitro studies indicate that 1 ng of oregovomab can bind 10 units of CA 125. Assuming 40 mL of plasma/kg of body weight, the injection of 2 mg of oregovomab into a 60 kg patient can bind ~8,333 U/mL of CA125 in serum. Since all of the ovarian cancer patients tested to date have had far less than 8333 U/mL of CA 125 in their serum, an injection of 2 mg of oregovomab is presumed to be more than sufficient to induce desired immune responses. Presuming the total HAMA response is an indication of anti-idiotypic induction, a 2 mg dose generates significant levels of anti-idiotypic antibodies sufficient to product the desired therapeutic benefits. Multiple injections of 2 mg of oregovomab at selected intervals appear to maintain the anti-idiotypic antibodies at the desired therapeutic level without causing any isotypic HAMA-induced toxicity.
Companies.: Antibody-based ImmunoTherapy (AIT) and OvaRex were developed by AltaRex Medical Corp., which was acquired by and merged into ViRexx Medical Corp. in Dec. 2004.
Abbott Labs. apparently originally manufactured Ovarex under contract to AltaRex, and may continue to supply product to Virexx. On Jan. 1, 2013, Abbott Labs. spun off its innovative pharmaceuticals business to Abbvie.
In April 2002, AltaRex licensed to Unither Pharmaceuticals, Inc., a subsidiary of United Therapeutics Corp. exclusive rights for development and commercialization of OvaRex (and four other monoclonal antibodies) worldwide, except for the European Union and certain other countries. Unither/United, thus, has exclusive rights in the U.S., North and South America, Asia and the Pacific Rim. In August 2003, the agreement was extended, granting Unither development rights for Germany.
Marketing rights in Italy, Spain, Portugal, Hungary, Poland, Czech Republic, Switzerland, Austria and certain other Eastern European countries were originally licensed to Dompé Farmaceutici. ViRexx retained responsibility for product development and registration of these territories. Dompe entered into a sublicensing agreement with FAES Farma S.A. for the commercialisation of OvaRex in Spain and Portugal.
European marketing was later transferred to Sigma-Tau Group. Virexx receives a net effective royalty of approximately 25% based on net sales of
OvaRex in the European and Middle Eastern countries.
Medison Pharma Ltd. and ViRexxx will establish a joint venture to market oregovomab in Israel and the Middle East. Genesis Pharma holds marketing rights in Greece, Turkey, Cyprus and the Balkans.
In 2006, Sigma-Tau Group assumed manufacturing responsibilities (at least for Europe), apparently initiating construction of its own facilities.
FDA class: Biologic BLA
Status: FDA has granted OvaRex both Orphan Drug Designation and Fast Track status (allowing submission of portions of its BLA as they are completed). OvaRex also has orphan status in the European Union.
OvaRex had expected to file a BLA in 2007/8.
In Dec. 2007, Unither halted its U.S. development of Ovarex after it failed in recent clinical trials.
Tech. transfer: AltaRex (now ViRexx) has received U.S. patents covering administration of a low dose of foreign antibody to patients expressing the CA 125 antigen; and photoactivation using ultraviolet light to modify antibodies and enhance specific beneficial immune responses.
U.S. 6,086,873, “Therapeutic composition and method of treatment ,” assigned to AltaRex, covers photoactivation, i.e., exposure to ultraviolet (UV) light, as a method to modify and increase immune responses to antibodies. The exemplary claim (no. 1) is, “A method of inducing an immune response in a vertebrate comprising exposing an antibody to ultraviolet light under conditions whereby the ultraviolet light exposes at least one reactive sulfhydryl on the antibody that does not change the biological function of the antibody to bind an antigen, to produce an altered antibody, wherein the altered antibody is unlabeled; administering the altered antibody to a host capable of generating an immune response to a native form of said antibody; allowing the host to generate an immune response to the altered antibody, whereby said immune response is greater than the immune response the host would produce against the native antibody.” The antibody is exposed to UV light at a wavelength from about 200-400 nm, at from about 0.1-1000 Joules/cm2, for about 10-30 minutes.
U.S. 6,241,985, “Method and composition for reconforming multi-epitopic antigens to initiate an immune response,” assigned to AltaRex concerns methods for induction of therapeutic immune responses to a multi-epitopic endogenous antigen that does not elicit an effective host immune response by contacting the antigen with a non-radiolabeled binding agent, e.g., monoclonan antibody, that specifically binds to an epitope on the antigen, forming a bound agent/antigen complex, such that host immune responses are elicited against a different epitope(s) on the antigen, with the antigen being CA125 and the binding agent being murine monoclonal antibody B43.13.
Pending applications assigned to AltraRex include U.S. 20070036798 and 20050063976, “Combination therapy for treating disease,” with claims covering OvaRex in combination with chemotherapy drugs for treatment of cancer.
Trials: OvaRex® MAb was the subject of one Phase II study examining combination chemo-immunotherapy in front-line treatment, and two randomized, double-blind and placebo controlled Phase III clinical trials examining immunotherapy during remission. In over 400 patients treate, OvaRex has demonstrated a benign safety profile. The human anti-mouse antibody (HAMA) responses to the murine antibody have not resulted in significant toxicity. The tolerability profile of oregovomab is similar to that of placebo, with no treatment-related toxicity reported.
Several Phase II trials with OvaRex as monotherapy or in combination with other chemotherapeutics have been completed across the U.S. and Canada. In its completed trials, OvaRex has shown anti-tumor activity following initial chemotherapy and in recurrent disease settings. Clinical trials have also been conducted in the European Union, but ViRexx suspended these “on the basis of commercial considerations.”
OvaRex did not meet its primary endpoint in a Phase II trial reported the Sept. 1, 2004 issue of the Journal of Clinical Oncology, 22:3507-3516, 2004. Patients (n = 145) with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to OvaRex or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR). Median time to relapse was not significantly different between treatments at 13.3 months for oregovomab and 10.3 months for placebo, i.e., OvaRex did not meet this primary endpoint. There were no differences in quality of life or in the frequency of adverse events between the groups, indicating a benign safety profile. Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. These patients had successful maximal surgical debulking (their tumors appeared to be well-excised), a good response to the first 2 cycles of chemotherapy as measured by serum CA125, a normal CA125 at the start of monoclonal antibody treatment, and absence of clinical disease. [Those patients whose tumor was not maximally debulked during initial surgery, those whose tumors failed to decrease in CA-125 after chemotherapy, or those who had clinical disease at the onset of the study, did not experience a statistically significant prolongation in progression-free survival]. For this SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287-1.025], with OvaRex showing significant efficacy. In patients in remission with biochemical relapse, the median time to relapse was significantly greater in OvaRex recipients with an immune response than in nonresponders (35.3 vs 7.5 weeks; p = 0.0011).
It has been reported that accrual for this trial was discontinued early and that the majority of the optimal patients ended up in the experimental arm, with most of the “less optimal” patients in the placebo arm. This imbalance could bias the results of the trial. The immune response, as measured by HAMA and seen in patients receiving the antibody, may reflect the fact that these particular patients were more immunocompetent and may have a better outcome regardless of therapy.
A similar study in patients without biochemical relapse has also reported that median time to relapse was greater in OvaRex recipients with an immune response than in those who did not respond (13.4 vs 4.7 months; p < 0.0001). Induction of the immune responses to OvaRex was measured by the development of human anti-mouse antibodies (HAMA), i.e. induction of antibodies to the foreign/non-self murine antibody protein. A HAMA response to oregovomab was associated with a significant advantage in disease free survival. These studies provided the basis for the ongoing confirmatory randomized U.S. Phase III trials. According to Virexx, "The Phase II study referred to above showed promising results for the use of OvaRex MAb in conjunction with front-line chemotherapy. Not only was OvaRex® MAb safe to use in this new setting, but cellular immune responses to the tumour antigen were seen.
Two pivotal U.S. Phase III IMPACT (IMmunotherapy Pivotal ovArian Cancer Trials) trials enrolling only “optimal” or SFLT patients during remission were initiated in Jan. 2003 by Unither Pharmaceuticals investigating OvaRex for the treatment of advanced ovarian cancer. The studies enrolled 367 ovarian cancer patients and assessed the efficacy of OvaRex mono- immunotherapy during the so-called "watchful waiting" period following front- line carboplatin-paclitaxel based chemotherapy. The program sought to confirm data observed in a subset analysis of a prior randomized phase II study, which suggested the potential of OvaRex to extend the time to disease relapse among patients who had successfully completed front-line therapy. These trials were conducted at over 60 sites across the U.S., with results intended to support registration of the antibody in the U.S., Europe and in other countries.
In Dec. 2007, The results of the IMPACT I and II Phase III trials indicated that while the use of OvaRex was safe, the outcomes were not statistically significant. However, there was no significant difference between active (standard of care followed by OvaRex) and control (standard of care followed by placebo) populations. The results of IMPACT I and II were consistent with each other. There were no statistically significant differences in safety profiles and the quality of life between the active and control groups.
In fall 2008, ViRexx reports it is evaluating the data and the assumptions underlying the OvaRex program prior to determining its next steps. A Phase II trial was being planned to evaluate adjunctive oregovomab plus cyclophosphamide chemotherapy in patients with advanced ovarian cancer having relapsed and undergone a second round of chemotherapy.
In fall 2008, Virexx reported, "The use of non-selective chemotherapy combined with targeted immunotherapy is being recognized as a new cancer treatment paradigm by the medical community. This new treatment mode represents an exciting partnering opportunity and ViRexx is pursuing discussions with several interested parties."
Medical: Administration involves a 20 minute intravenous infusion with a low dose (2 mg) of oregovomab, 4 to 5 times/year.
Marketing: Virexxx has reported that OvaRex may attain a market of $800 million/year as a second-line “consolidation” therapy for ovarian cancer.
Index Terms:
Companies involvement:
Full monograph
301 CA125 Mab
Nomenclature:
OvaRex [TR]
Oregovomab [USAN INN]
immunoglobulin G1, anti-(human CA125 (carbohydrate antigen)) (mouse monoclonal B43.13gamma1-chain), disulfide with mouse monoclonal B43.13kappa-chain, dimer [CAS]
213327-37-8 [CAS RN]
Antibody-based ImmunoTherapy (AIT) [SY]
B43.13 [SY]
MAb B43.13 [SY]
MAb-B43.13 [SY]
ATCC PTA-1883 [ATCC]
FDA Class: Biologic BLA
biopharmaceutical products
murine (mouse) materials used
antibodies (see also immune globulins; monoclonal antibodies)
ATCC HB8832
autologous cells, human
C7F7 monoclonal antibody
murine (mouse) hybridoma cells
murine feeder cells
phosphorothioates
tumor necrosis factor-2 receptor (TNFR2)
antibodies (see also immune globulins; monoclonal antibodies)
leukocyte removal
phosphorothioates
U.S. Standard Rabies Vaccine
U.S. Standard Rabies Vaccine
apheresis (hemapheresis)
North American coral snake
orphan status
EU000 Not yet/Never filed with EU
SM200 Not Available/Not Marketed
US000 never filed/no plans
EM999 Not Available/Not Marketed in EU
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