Clinical Parameters for Determining Hematologic Toxicity Prior to Radioimmunotherapy
a technology of hematologic toxicity and clinical parameters, which is applied in the field of clinical parameters for determining hematologic toxicity prior to radioimmunotherapy, can solve the problems of induction of immune responses, non-human monoclonal antibodies, and lack of human effector functionality of non-human monoclonal antibodies, and achieve accurate prediction and convenient prediction.
Inactive Publication Date: 2007-06-28
BIOGEN INC
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Benefits of technology
[0036] Dosage amounts of radiolabeled antibody will of course depend upon the particular patient, the particular antibody, the particular target, and the particular radiolabel. Also pertinent is the extent of initial bone marrow involvement and the efficacy of the prior treatment with unlabeled depleting antibody. But for 90Y-labeled anti-CD20 antibody and particularly Y2B8, preferred dosages will range from about 0.1 to 0.5 mCi / kg. Appropriate dosages for any particular antibody may be determined through routine optimization by the skilled practitioner.
[0038] One of the underlying observations that makes the methods disclosed herein so useful is that patients having bone marrow involvement are particularly susceptible to radioimmunotherapy when the radiolabeled antibodies are targeting cells in the bone marrow. Radioisotopes in the bone marrow ablate normal progenitor cells which may not even express the targeted cell surface molecule, thereby depleting the population of immune cells which would normally facilitate reconstitution of the immune system following radioimmunotherapy. Moreover, patients who do have bone marrow involvement do not benefit from autologous bone marrow harvest and transplantation, since such transplantation merely reinfuses tumor cells back into the patient. Thus, having a routine method whereby bone marrow involvement is identified and rectified prior to radioimmunotherapy would be a valuable addition to the field of lymphoma treatments. In this regard, the clinical parameters disclosed herein would likely also indicate the extent of bone marrow toxicity experienced by antibodies labeled with other cytotoxic moieties, e.g. toxins. Thus, the parameters disclosed herein may also be used to predict and deter toxicity and bone marrow ablation due to administration of cytotoxic antibodies.
[0044] These results suggest that clinical parameters including baseline platelet count and degree of bone marrow involvement with lymphoma may be able to replace dosimetry for safe administration of Y2B8 and other radiolabeled antibodies in patients and NHL. Hematologic toxicity with Y2B8 is clearly related to therapeutic antibody targeting of lymphoma cells residing in the marrow.
Problems solved by technology
A potential problem with this approach is that non-human monoclonal antibodies (e.g., murine monoclonal antibodies) typically lack human effector functionality, i.e., they are unable to, inter alia, mediate complement dependent lysis or lyse human target cells through antibody dependent cellular toxicity or Fe-receptor mediated phagocytosis.
Furthermore, non-human monoclonal antibodies can be recognized by the human host as foreign proteins; therefore, repeated injections of such foreign antibodies can lead to the induction of immune responses leading to harmful hypersensitivity reactions.
Furthermore, internalization of labeled antibodies is not required for cell killing, and the local emission of ionizing radiation should be lethal for adjacent tumor cells lacking the target antigen.
The slow introduction of radiolabeling kits to the market may have been due to the poor incorporation efficiencies demonstrated by some known labeling protocols, and the subsequent need to column purify the reagent following the radiolabeling procedure.
The delay in development of such kits might also in part be due to the previous lack of accessibility to pure commercial radioisotopes which may be used to generate efficiently labeled products absent subsequent purification.
Alternatively, perhaps the reason such kits are generally unavailable is the actual lack of antibodies which have been able to achieve either the approval or the efficacy that Rituxan® has achieved for the treatment of lymphoma in human patients.
Indeed, injecting unbound radiolabel into the patient would not be desirable.
The need for additional purification steps renders the process of radiolabeling antibodies in the clinical setting an impossibility, particularly for doctors who have neither the equipment nor the time to purify their own therapeutics.
Furthermore, radiolabeled proteins may be inherently unstable, particularly those labeled with radiolytic isotopes such as 90Y, which have the tendency to cause damage to the antibody the longer they are attached to it in close proximity.
In turn, such radiolysis causes unreliable efficiency of the therapeutic due to loss of radiolabel and / or reduced binding to the target antigen, and may lead to undesired immune responses directed at denatured protein.
Yet without the facilities for labeling and purifying the antibodies on site, clinicians have had no choice but to order therapeutic antibodies already labeled, or have them labeled off site at a related facility and transported in following labeling for administration to the patient.
All such manipulations add precious time to the period between labeling and administration, thereby contributing to the instability of the therapeutic, while in effect decreasing the utility of radiolabeling kits in the clinical setting.
However, such protocols were not able to achieve the level of incorporation that the present inventors have achieved using the protocols disclosed herein, which have resulted in incorporation efficiencies of at least 95%.
However, there still remain some impediments to convenient clinical use of immunotherapeutics radiolabeled with beta-emitting radioisotopes such as 90Y.
Unlike 111In, 90Y cannot be used for imaging purposes due to the lack of gamma radiation associated therewith.
This requirement for dosimetric evaluation prior to administration of a therapeutic antibody detracts from the convenience of using immunotherapy to treat patients in the clinical setting, wastes precious time during which the patient could be undergoing treatment which will actually help alleviate the disease, and increases the exposure to radioactivity for both the patient and the doctor.
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[0027] The present invention encompasses methods of predicting the severity of hematologic toxicity which would result from administration of a radiolabeled antibody to a cancer patient, particularly patients having B cell lymphoma, and using such a prediction to deter or decrease such hematological toxicity prior to administering the radiolabeled antibody. For instance, it has been found that two clinical parameters in particular, baseline platelet count and degree of bone marrow involvement, were better predictors of hematological toxicity in non-Hodgkins B cell lymphoma patients than were dosimetry parameters.
[0028] The methods of predicting, then deterring, the toxicity of radioimmunotherapeutics disclosed herein may comprise a variety of steps, including: (a) measuring the degree of bone marrow involvement in a baseline biopsy or baseline platelet count; and (b) administering a therapeutically effective amount of unlabeled chimeric or human antibody if said baseline bone marro...
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Abstract
New clinical parameters are reported which may serve as predictors of the hematological toxicity associated with therapeutic radiolabeled antibodies, particularly those antibodies which target lymphoma cells which have a tendency to localize to the bone marrow.
Description
FIELD OF INVENTION [0001] The present invention reports new clinical parameters for predicting the hematological toxicity which can be expected upon administering a therapeutic radiolabeled anti-CD20 antibody, as well as other therapeutic antibodies which have the potential to target immune cells. The clinical parameters of the present invention are useful alternatives to performing dosimetry trials with gamma-emitting radiolabeled antibodies prior to therapy. BACKGROUND OF THE INVENTION [0002] The immune system of vertebrates (for example, primates, which include humans, apes, monkeys, etc.) consists of a number of organs and cell types which have evolved to: accurately and specifically recognize foreign microorganisms (“antigen”) which invade the vertebrate-host; specifically bind to such foreign microorganisms; and, eliminate / destroy such foreign microorganisms. Lymphocytes, as well as other types of cells, are critical to the immune system. Lymphocytes are produced in the thymus...
Claims
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IPC IPC(8): G01N33/574A61K39/395A61K51/00A61P35/00C07K16/28
CPCA61K51/1027A61K2039/505C07K16/2887C07K16/2896G01N33/5091G01N33/5094A61P35/00
InventorRAESTETTER, WILLIAMWHITE, CHRISTINE A.
OwnerBIOGEN INC