Table 1 - uploaded by Mark C Glassy
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A panel of four natural human monoclonal IgG antibodies derived from B lymphocytes isolated from regional draining lymph nodes of cancer patients has been developed and characterized. The four human antibodies are termed, RM1, RM2, RM3, and RM4. The immunoreactivity of this panel of four human antibodies is restricted to tumor cells. Individually,...
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... Even a cocktail of 3 or 4 antibodies was shown to increase bioactivity against tumor cell lines [11]. After observing that combinations of monoclonal antibodies increased effectiveness the authors suggested that cocktails of antibodies may be useful in the clinic [12]. ...
Background: Antibodies that target a single tumor antigen fail to cure stage IV cancer patients due to tumor heterogeneity resulting in variable expression of antigen. Tumor cells with insufficient binding of antibody will not undergo antibody induced cytotoxicity. We describe targeting multiple tumor-specific antigens that resulted in homogeneous dense binding to mouse melanoma cells and significant tumor growth inhibition. Methods: Surface-related tumor-specific mutations on B16-F10 cells were identified. Peptides containing the single amino acid mutation were synthesized for 9 different neoantigens. Rabbits were vaccinated with each of these peptides and high affinity polyclonal antibodies to each peptide were obtained. The 9 antibodies were combined as a cocktail and mice with implanted B16-F10 cells were treated with and without PD1 inhibitor. Results: Even a single dose of the antibody cocktail inhibited tumor growth and prolonged survival. PD1 inhibitor alone had little effect on tumor growth. The antibody cocktail plus PD1 inhibition increased tumor response and 4 doses of the cocktail completely prevented tumor growth in 50% of the mice. Complete responses were durable. The complete responders were highly resistant to tumor re-challenge at 6 months. No adverse events were identified in the antibody treated mice. Conclusions: Multiple tumor-specific cell surface-related neoantigens were abundant in B16-F10 cells. Antibodies to 9 of these neoantigens had variable binding but when combined had dense homogeneous binding. Even one dose of this cocktail of 9 antibodies improved survival and when multiple does were combined with PD1 inhibition 50% of the mice were rendered permanently tumor free.
... Can-cer patients can generate tumor-specific B lymphocytes which can be isolated to develop human mAbs against tumor-associated antigens. In cancer, the best source of anti-tumor antibodies is from sentinel lymph nodes [6,7]. Pritumumab, the therapeutic antibody reviewed here, is a classic example of a natural human anti-cancer antibody. ...
Immunotherapy is now at the forefront of cancer therapeutic development. Gliomas are a particularly aggressive form of brain cancer for which immunotherapy may hold promise. Pritumumab (also known in the literature as CLNH11, CLN-IgG, and ACA-11) was the first monoclonal antibody tested in cancer patients. Pritumumab is a natural human monoclonal antibody developed from a B lymphocyte isolated from a regional draining lymph node of a patient with cervical carcinoma. The antibody binds ecto-domain vimentin on the surface of cancer cells. Pritumumab was originally tested in clinical trials with brain cancer patients in Japan where it demonstrated therapeutic benefit. It was reported to be a safe and effective therapy for brain cancer patients at doses 5-10 fold less than currently approved antibodies. Phase I dose escalation clinical trials are now being planned with pritumumab for the near future. Here we review data on the development and characterization of pritumumab, and review clinical trails data assessing immunotherapeutic effects of pritumumab for glioma patients.
... The general properties of pritumumab antibody are listed in Table 1 with their respective reference. This antibody may reflect the natural immune response to cancer antigens [5,6] and be involved in tumor biology [7,8]. ...
... The antigen is found on cells of ectodermal (brain), endodermal (colon, pancreas), and mesodermal (reproductive) origin. This is an interesting comment on the natural human immune response to cancer antigens [5,8]. Of particular specificity and interest was the binding of pritumumab to brain tumor tissues [17,20,26,27]. ...
... Since the antibody was derived from a sentinel lymph node [3,7] this lends more credence to that aspect of human cancer biology. Patients do generate a humoral immune response to their own tumor antigens [1,5,8] and pritumumab appears to be one of these antibodies. Since tumors do grow this questions either the immune efficiency of the generated antibody response or perhaps the tumor cells outgrow the speed of the amount of antibodies generated by cancer patients necessary to eradicate their cancer cells. ...
Pritumumab is a human IgG1 kappa antibody that has been derived from a B-cell isolated from a regional draining lymph node of a patient with cervical carcinoma. Specificity analysis of the antibody with human tissues showed the antigen, altered tumor-associated vimentin, to be highly restricted to various cancers and not normal cells and tissues. In various clinical trials in Japan 249 patients with brain cancer were treated with pritumumab. The overall response rate was between 25-30% with several survivors beyond 5-years post-treatment. The patients were on a low dose regimen of 1mg given twice a week for a course of 24 weeks for a total dose of 48 mgs per course. Pritumumab appears to be a safe and effective therapy in patients with malignant gliomas.
... Lymph node/Large cell carcinoma WT WT No No Yes (Carretero et al., 2004;Glassy et al., 2007;Phelps et al., 1996), www.sanger.ac.uk ...
Background:
Antibodies that target a single tumor antigen fail to cure stage IV cancer patients due to tumor heterogeneity resulting in variable expression of antigen. Tumor cells with insufficient binding of antibody will not undergo antibody induced cytotoxicity. We describe targeting multiple tumor-specific antigens that resulted in homogeneous dense binding to mouse melanoma cells and significant tumor growth inhibition.
Methods:
Surface-related tumor-specific mutations on B16-F10 cells were identified. Peptides containing the single amino acid mutation were synthesized for 9 different neoantigens. Rabbits were vaccinated with each of these peptides and high affinity polyclonal antibodies to each peptide were obtained. The 9 antibodies were combined as a cocktail and mice with implanted B16-F10 cells were treated with and without PD1 inhibitor.
Results:
Even a single dose of the antibody cocktail inhibited tumor growth and prolonged survival. PD1 inhibitor alone had little effect on tumor growth. The antibody cocktail plus PD1 inhibition increased tumor response and 4 doses of the cocktail completely prevented tumor growth in 50% of the mice. Complete responses were durable. The complete responders were highly resistant to tumor re-challenge at 6 months. No adverse events were identified in the antibody treated mice.
Conclusions:
Multiple tumor-specific cell surface-related neoantigens were abundant in B16-F10 cells. Antibodies to 9 of these neoantigens had variable binding but when combined had dense homogeneous binding. Even one dose of this cocktail of 9 antibodies improved survival and when multiple doses were combined with PD1 inhibition 50% of the mice were rendered permanently tumor free.
The natural human immune response is an oligoclonal response. Although polyclonal antibody preparations have been used in the clinic, oligoclonal antibody preparations will eventually replace conventional polyclonal antibodies because of their advantages of more control and less variability. The same can also be perceived of monoclonal antibodies in that for clinical applications they will be in combinations of antibodies (oligoclonal) rather than monotherapy monoclonals that provide better control and regulate the immune response. For most diagnostic assays, mAbs will continue to be the reagent of choice. However, recombinant polyclonal antibodies manufactured through newer technologies such as Simplex and Sympless to identify and manufacture antigen-specific recombinant human polyclonal antibodies could make a significant impact in the arena of polyclonal antibodies as therapeutic drugs for infectious and autoimmune diseases, including cancer. While mono and oligoclonal antibodies have proved to be of great significance from cost point of view, oligoclonal antibodies are expected to be economical therapeutics.
The use of intravenous immunoglobulin (IVIG) concentrated from pooled healthy donors' plasma has gained increasing popularity. IVIG therapy has become important as a replacement therapy in primary and acquired humoral immunodeficiencies, and it has been extended to autoimmune, neurodegenerative and inflammatory conditions and transplantation therapy. Recurrent pregnancy failure and cancer are rather new platforms, where IVIG has shown its beneficial effects. This manuscript is focused on these two off-labelled usages. The immunomodulatory mechanisms of IVIG therapy appear as a coordinated orchestration of different functions, resulting in a synergistic effect. Treatment monitoring and detailed molecular analyses reveal how such treatments may interfere with disease pathogenesis. These finding may foster the development of novel therapeutic and/or preventive strategies. Studying this field with bidirectional bench-to-bedside and bedside-to-bench approaches fit well into 'the two-way road' paradigm of translational medicine.
