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Racotumomab – a Novel Anti-Idiotype Monoclonal Antibody Vaccine for the Treatment of Cancer

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Racotumomab – a Novel Anti-Idiotype Monoclonal Antibody Vaccine for the Treatment of Cancer Drugs of Today 2014, 50(4): 301-307 Copyright © 2014 prous Science, S.a.U. or its licensors. all rights reserved. CCC: 1699-3993/2014 DoI: 10.1358/dot.2014.50.4.2116670 Monograph raCoTUMoMaB – a noVEL anTI-IDIoTYpE MonoCLonaL anTIBoDY VaCCInE For ThE TrEaTMEnT oF CanCEr Z. Gajdosik Thomson reuters, Barcelona, Spain CONTENTS Summary . .301 Background . .301 preclinical data . .302 Clinical studies . .303 Safety . .305 Indications and current development . .305 references . .306 SUMMARY strated high immunogenicity and low toxicity and it Racotumomab is a murine gamma-type anti-idiotype advanced to further clinical testing as a treatment for monoclonal antibody that specifically induces an antibody patients with non-small cell lung cancer (NSCLC). On the response against Neu-glycolyl GM3 ganglioside basis of promising results in a phase II/III study, racotu - (NeuGcGM3), which is overexpressed in several solid momab was launched in 2013 in Cuba and Argentina as tumors. It is adjuvanted with aluminum hydroxide for an intradermal injection for the treatment of patients with intradermal administration as a cancer vaccine (racotu - advanced stage NSCLC. momab-Alum, known commercially as Vaxira ). Key words: racotumomab – neugcgM3 – Cancer vac - Racotumomab is currently being evaluated for a number cine – non-small cell lung cancer of cancer indications, including melanoma, breast a®nd lung cancer. In early clinical trials, racotumomab demon - BACKGROUND The development of immune-based therapies for the Correspondence: Zuzana gajdosik , Thomson reuters, Barcelona, Spain. treatment of cancer has become an attractive option as E-mail: [email protected] the specificity of these therapies has the advantage of 301 raCoTUMoMaB Z. Gajdosik inducing fewer side effects than the conventional non - ly against the tumor antigen neugcgM3. The antibody specific chemotherapy and radiotherapy treatments. triggers a strong anti-idiotypic antibody (ab3) response, Thus far, the development of passive immunotherapy, which has the same antigenic specificity as ab1 such as monoclonal antibodies (Mabs) or cytokines, has (p3), mimicking the three-dimensional structure of the proven effective and efforts are now being made to N-glycolyl, giving rise to a specific immune response develop vaccines that would induce an active immune against the tumor antigen neugcgM3 and reducing the protection by boosting the host’s immune defense potential risk of immune crossreactivity. This review against tumor-associated antigens (Taas). Cancer vac - describes some of the preclinical and clinical data for cines have been designed to stimulate antitumor this novel oncolytic vaccine candidate. responses targeting tumor-specific Taas while preserv - ing surrounding tissue from nonspecific toxicity. Since PRECLINICAL DATA most Taas are self-antigens and the body eventually BaLB/c mice were immunized seven times at 14-day builds up immune tolerance against them, the develop - intervals with intraperitoneal injections of 50 g racotu - ment of vaccines against these oncoproteins has been momab coupled to keyhole limpet hemocyanin (KLh), challenging. one of the strategies to overcome this racotumomab alone, the carrier KLh alone or the immune tolerance barrier consists of the use of anti-idio - immunological adjuvant alone (pBS control). Three of typic Mabs, also referred to as ab2, to function as anti - the doses were administered before and four dµoses after gen surrogates and as such modulate the immune subcutaneous inoculation with F3II mammary tumor response. Immunization with a given antigen leads to cells. In the control animals, the tumors grew by invad - the generation of antibodies (ab1) directed against this ing the muscular and adipose layers of the subcutis, and specific antigen, and ab1 antibodies can then be used to at day 30, the tumor cells invaded the dermis and the generate a series of anti-idiotypic antibodies (ab2) dermal papillae causing necrosis in the epidermal layer directed against these ab1 antibodies. The resulting ab2 and visible ulceration on the surface of the tumors. antibodies are often able to mimic the three-dimension - Tumor incidence was 100% and the latency was similar al structure of the native antigen and can therefore be in all groups. a significant decrease in subcutaneous used as immunogens to induce a specific immune tumor growth was seen in the racotumomab/KLh- response similar to the one that would be induced by the immunized animals, while no differences were seen in initial antigen (1, 2). tumor growth between the control mice and the mice an additional advantage of the anti-idiotypic vaccines is treated with racotumomab or KLh alone. Immunization that these vaccines are also able to target antigens of a with racotumomab/KLh also significantly reduced the non-protein origin. Tumor-associated carbohydrate anti - spontaneous dissemination to lungs of the F3II mamma - gens (TaCa) have been identified as a subset of Taas of ry tumor cells. In the second portion of the experiment, carbohydrate nature that are specifically expressed on C57BL/6 mice were inoculated with B16 murine tumor tissue as compared to normal tissue due to an melanoma cells, and 10 or 14 days post-inoculation the aberrant glycosylation in tumor cells. additionally, it has animals were injected with 10 g intravenous racotu - been demonstrated that TaCas play an essential role in momab, an irrelevant Mab or pBS alone. The animals metastasis induction and tumor invasiveness. given racotumomab had a significantly reduced number of lung metastases compared with the mice that gangliosides are a group of TaCas that have gained spe - received pBS. Lymph node cellµs from naive mice and cial attention as novel targets for cancer immunothera - from animals immunized with racotumomab were chal - py, based on the qualitative and quantitative changes lenged in vitro with the anti-idiotype Mab or the irrele - they suffer during malignant transformation and due to vant antibody in order to evaluate the ability of racotu - their importance for tumor biology (3, 4). gangliosides, momab to induce proliferation of lymphocytes to its especially neu-glycolyl gM3 ganglioside (neugcgM3), idiotype. no proliferative response was seen in either of are not expressed in normal human cells but are overex - the two groups of cells after challenge with different pressed in several solid tumors. In metastatic lesions, the concentrations of the anti-idiotype Mab (6). presence of neugcgM3 reaches 73.4% of total lipid bound sialic acid (5). racotumomab (formerly known as The nature of the idiotope defined by racotumomab was 1E10) is a murine gamma-type anti-idiotype Mab (ab2 evaluated using a phage-displayed random peptide Mab) specific to the ab1 Mab p3 able to react specifical - library. Seven different phagotopes were isolated and all 302 ThoMSon rEUTErS – Drugs of Today 2014, 50(4) Z. Gajdosik raCoTUMoMaB the sequences were found to bear the basic amino acid- The results of this study demonstrated that biweekly rich motifs Kppr or rrrr/K. It was observed that the p3 treatment with racotumomab (50-200 g) was highly Mab completely inhibited the binding of racotumomab effective against the 3LL lung tumor nodules. to phage peptides, suggesting that the peptides are pos - additionally, the combination of pemetrexed-based sible mimotopes of the idiotope recognized by anti-idio - chemotherapy (100 mg/kg weekly) with the biweekly typic antibodies in p3. previous studies had shown that doses of racotumomab showed a significµant synergistic p3’s idiotype is autoimmunogenic and shared by anti - effect as compared to each treatment alone, when eval - bodies with different specificities, and now it has been uated in this mouse model of nSCLC. The therapeutic demonstrated that the p3 Mab is able to activate a net - effect of racotumomab was associated with an increase work cascade involving autologous anti-idiotypic and of CD4 + and CD8 + cell infiltration, reduced angiogenesis anti-anti-idiotypic T cells. The results also revealed the and tumor cell apoptosis in lung nodules. The results of immunodominance of p3’s heavy chain CDr3 (h-CDr3), this study support the use of chemo-immunotherapy showing that it behaves as a potential regulatory combinations for the treatment of nSCLC (5, 10). idiotope, simultaneously involved in the interaction of p3 Mab with anti-idiotypic B and T cells (7). CLINICAL STUDIES In F3II tumor-bearing mice, the administration of racotu - The clinical efficacy of racotumomab was evaluated in a momab (100 g) in combination with low-dose number of early clinical trials. The first phase I study was cyclophosphamide (150 mg/m 2) led to a significant designed to investigate the safety of aluminium hydrox - reduction in the F3II mammary carcinoma growth. It was ide-precipitated racotumomab in patients with observed that immunization with racotumomab potenti - advanced malignant melanoma. The study enrolled a ated the antiangµiogenic effect of low-dose cyclophos - total of 20 subjects, who were treated with 6 intradermal phamide and it also led to a significant reduction in injections of racotumomab, given at 2-week intervals. splenic myeloid cells gr1 +/CD11b + which are associated Seventeen of the patients received at least 4 doses of the with a suppressor phenotype. These data demonstrated vaccine and 16 of the immunologically evaluable sub - a combinatorial therapeutic effect based on the comple - jects developed ab3 antibodies expressing p3 epitopes, mentary antiangiogenic
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