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American Journal of Clinical Oncology Jul 2022Human leukocyte antigen (HLA)-DR, a member of the major histocompatibility complex class II antigen family, is a target for antibody-based therapeutics. Apolizumab...
BACKGROUND
Human leukocyte antigen (HLA)-DR, a member of the major histocompatibility complex class II antigen family, is a target for antibody-based therapeutics. Apolizumab (Hu1D10, Remitogen), a humanized IgG1 monoclonal anti-HLA-DR ß-chain antibody targets the antigen, 1D10, expressed on a wide variety of hematologic and solid tumor malignancies. In this Phase 1 trial, the maximum tolerated dose and dose-limiting toxicity of weekly apolizumab in patients with advanced solid tumor malignancies were determined.
PATIENTS AND METHODS
Eligible patients with refractory solid tumors were initially screened for ID10 Ag on their tumor. Patients whose tumors expressed 1D10 were administered apolizumab 0.5, 1.0, 1.5, or 3.0 mg/kg intravenously over 90 minutes weekly for 4 consecutive weeks, followed by a 4-week break, and assessment of response. Patients whose disease had not progressed were offered additional treatment.
RESULTS
Tumors from 75 patients were screened for 1D10 Ag of which 17 patients were positive and underwent treatment. The first 3 dose levels were well-tolerated. Dose-limiting toxicities of grade 3 infusion-related hypersensitivity reactions and grade 3 headache and hypertension occurred in 2 patients, respectively, at apolizumab 3.0 mg/kg. Four patients, 1 each with breast carcinoma, melanoma, renal cell carcinoma, and sarcoma had stable disease for a median of 15 weeks (range: 12 to 19 wk).
CONCLUSION
Apolizumab can be administered safely at a maximum tolerated dose of 1.5 mg/kg for 4 consecutive weeks. Adverse events and limited clinical data in both hematologic and solid tumor malignancies resulted in discontinuation of clinical development of apolizumab. HLA-DR remains an interesting immunotherapeutic target.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma, Renal Cell; HLA-DR Antigens; Humans; Kidney Neoplasms; Maximum Tolerated Dose; Neoplasms
PubMed: 35700081
DOI: 10.1097/COC.0000000000000924 -
Seminars in Oncology Feb 2002Clinical activity of anti-CD20 monoclonal antibodies both in the unlabeled (rituximab [Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San... (Review)
Review
Clinical activity of anti-CD20 monoclonal antibodies both in the unlabeled (rituximab [Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA]) and radiolabeled forms, as well as radioimmunoconjugates targeting other antigens, has resulted in the exploration of alternative targets for immunotherapeutic strategies in lymphoma. We report on the rationale for and initial efforts in the development of two unlabeled, humanized monoclonal antibodies directed against molecules commonly expressed in B-cell malignancies. hLL2 (epratuzumab; Immunomedics, Inc, Morris Plains, NJ) binds to the CD22 antigen, while Hu1D10 (apolizumab; Protein Design Labs, Inc, Fremont, CA) reacts with a polymorphism on the HLA-DR beta chain. Preclinical studies and early clinical evaluations suggest that these agents have a potential role as novel therapeutic targets for lymphoma with acceptable toxicity profiles. Further efforts will explore optimal clinical settings for their use, as well as define treatment regimens either as single agents or in combination with chemotherapy or other biologics.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; Cell Adhesion Molecules; Clinical Trials as Topic; HLA-DR Antigens; Humans; Immunotherapy; Lectins; Lymphoma, Non-Hodgkin; Sialic Acid Binding Ig-like Lectin 2
PubMed: 11842393
DOI: No ID Found -
Leukemia & Lymphoma Dec 2009
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Area Under Curve; Fatigue; Fever; HLA-DR Antigens; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Metabolic Clearance Rate; Myocardial Ischemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 19886843
DOI: 10.3109/10428190903370379 -
Leukemia & Lymphoma Oct 2006Apolizumab is a humanized monoclonal antibody against a polymorphic epitope on HLA DRbeta that demonstrated evidence for therapeutic activity in follicular lymphoma...
A humanized HLA-DR antibody (hu1D10, apolizumab) in combination with granulocyte colony-stimulating factor (filgrastim) for the treatment of non-Hodgkin's lymphoma: a pilot study.
Apolizumab is a humanized monoclonal antibody against a polymorphic epitope on HLA DRbeta that demonstrated evidence for therapeutic activity in follicular lymphoma patients. In pre-clinical studies, we previously reported that granulocyte colony-stimulating factor (G-CSF) treatment significantly enhanced lymphoma cell killing by HLA class II antibodies, including apolizumab. These results suggested a combination trial of apolizumab and G-CSF (filgrastim). In this trial, we treated six patients with relapsed or refractory 1D10-positive non-Hodgkin's lymphoma with filgrastim and variable doses of apolizumab ranging from 0.15 to 1.5 mg/m2. The combination was clinically well tolerated, with only two patients experiencing grade III/IV hematological toxicity (thrombocytopenia and autoimmune hemolytic anemia). Another patient developed a pruritic skin rash, which was probably a treatment-related grade II skin toxicity. Interestingly, two patients with follicular lymphoma who received intensified apolizumab treatment on a three times weekly schedule experienced prolonged stabilization of their disease for 12 and more than 36 months. In conclusion, this small pilot study suggests that a combination of HLA class II antibodies and G-CSF is clinically feasible.
Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; HLA-DR Antigens; Humans; Leukocytes; Lymphoma, Non-Hodgkin; Male; Middle Aged; Pilot Projects; Recombinant Proteins
PubMed: 17071489
DOI: 10.1080/10428190600757944 -
Leukemia & Lymphoma Dec 2009Apolizumab (Hu1D10), a humanized monoclonal anti- Human leukocyte antigen -DR beta-chain antibody, mediates apoptosis of chronic lymphocytic leukemia (CLL) cells in...
Apolizumab (Hu1D10), a humanized monoclonal anti- Human leukocyte antigen -DR beta-chain antibody, mediates apoptosis of chronic lymphocytic leukemia (CLL) cells in vitro. We conducted a phase I/II dose-escalation study of thrice-weekly apolizumab (1.5, 3.0, 5.0 mg/kg/dose) for 4 weeks in relapsed CLL. Two of six patients at 5.0 mg/kg/dose developed treatment-related dose-limiting toxicity (aseptic meningitis, hemolytic uremia). Other toxicities included infusion toxicity, urticaria, and headache. Eleven patients were enrolled in a phase I/II expansion to evaluate the maximum tolerated dose (MTD) of 3.0 mg/kg/dose. In total, 23 patients were enrolled (22 CLL, 1 ALL). Nineteen patients with CLL were treated at or above the MTD. One partial response was observed, and three patients had stable disease exceeding 6 months. Pharmacokinetic analysis demonstrated a dose-dependent C(max) increase and serum antibody accumulation after week 1 of therapy. Given the toxicity and lack of efficacy in this and other trials in lymphoma and solid tumors, further development of apolizumab was discontinued.
Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Fever; HLA-DR Antigens; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Metabolic Clearance Rate; Middle Aged; Myocardial Ischemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 19860603
DOI: 10.3109/10428190903186486 -
Current Cancer Drug Targets Mar 2008For many years, alkylating agents and purine nucleoside analogs (PNA) have been considered the drug of choice for treatment of chronic lymphocytic leukemia (CLL). More... (Review)
Review
For many years, alkylating agents and purine nucleoside analogs (PNA) have been considered the drug of choice for treatment of chronic lymphocytic leukemia (CLL). More recently the introduction of monoclonal antibodies (mAb), especially rituximab directed against CD20 and alemtuzumab directed against CD52, has renewed interest in CLL therapy. Over the last few years, several new mAbs directed against lymphoid cells have been developed and investigated in preclinical studies and clinical trials. Some of them are highly active in CLL. New mAbs directed against CD20 include human mAb ofatumumab (HuMax CD20), IMMU-106 (hA20) which has a >90% humanized framework and GA-101, a novel third - generation fully humanized and optimized mAb. These agents are highly cytotoxic against B-cell lymphoid cells and are evaluated in CLL. Lumiliximab (anti-CD23 mAb) is a genetically engineered macaque-human immunoglobulin (Ig) A1. This antibody showed high activity and good tolerability in phase I clinical trial and is evaluated in phase I/II clinical trials as a single agent and in combination. Epratuzumab is a humanized anti-CD22 mAb currently used in clinical trials for treatment of non-Hodgkin lymphoma and autoimmune disorders. Further studies are needed to elucidate the role of this agent in CLL. Apolizumab (HU1D10) is a humanized IgG1 antibody specific for a polymorphic determinant found on the HLA-DRbeta chain. Preclinical and early clinical studies suggest that this mAb has some activity in CLL. HCD122 (CHIR-12.12) and SGN-40 are anti-CD40 mAbs which induce cytotoxicity against CLL cells. Phase I study has shown a favorable safety profile and some activity of HCD122 in pretreated CLL patients. Immunotoxins, especially BL22, LMP-2 and denileukin diftitox, are also being evaluated in lymphoid malignancies and seem to be active in CLL. Finally, antiangiogenic mAbs, especially bevacimzumab, have a potential therapeutic role in this disease. In this review, new mAbs, potentially useful in CLL are presented.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell
PubMed: 18336199
DOI: 10.2174/156800908783769319 -
Methods and Findings in Experimental... 2003Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABT-510, ABX-EGF, acetyldinaline, ACIDFORM, acyline, afeletecan hydrochloride, anecortave acetate, apolizumab, l-arginine hydrochloride, asimadoline, atazanavir sufate, atlizumab; BMS-181176, BMS-188667; CAB-175, carnosine, CDP-870, CEP-701, CEP-7055, CGC-1072, ChimeriVax-JE, ciclesonide, cilomilast, clofarabine, combretastatin A-4 phosphate, cryptophycin 52; Duloxetine hydrochloride; E-5564, eculizumab, elcometrine, emtricitabine, ENO, epratuzumab, eszopiclone, everolimus; Fampridine, flurbiprofen nitroxybutyl ester; Garenoxacin mesilate, gestodene, GI-181771, gimatecan, gomiliximab; Halofuginone hydrobromide, hGH, hLM609; ICA-17043, IL-1 receptor type II, IMC-1C11, iodine (I131) tositumomab, irofulven, ISAtx-247; J591; L-778123, lanthanum carbonate Lasofoxifene tartrate, LDP-02, LE-AON, leteprinim potassium, lintuzumab, liraglutide, lubiprostone, lumiracoxib, lurtotecan, LY-450108, LY-451395; MAb G250, magnesium sulfate, MDX-210, melatonin, 2-methoxy-estradiol, monophosphoryl lipid A; NM-3, nolpitantium besilate; Ocinaplon, olpadronic acid sodium salt, oral heparin; Palonosetron hydrochloride, pemetrexed disodium, PI-88, picoplatin, plevitrexed, polyphenon E, pramlintide acetate, pregabalin, prinomastat, pyrazoloacridine; Resiniferatoxin, rhEndostatin, roxifiban acetate; S-18886, siplizumab, sitaxsentan sodium, solifenacin succinate, SU-11248, SU-6668; Talampanel, TAPgen, testosterone transdermal gel, trabectedin; VEGF-2 gene therapy, visilizumab; ZD-6416, ZD-6474.
Topics: Clinical Trials as Topic; Humans
PubMed: 12949633
DOI: No ID Found -
Seminars in Oncology Feb 2002Clinical activity of anti-CD20 monoclonal antibodies both in the unlabeled (rituximab [Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San...
Clinical activity of anti-CD20 monoclonal antibodies both in the unlabeled (rituximab [Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA]) and radiolabeled forms, as well as radioimmunoconjugates targeting other antigens, has resulted in the exploration of alternative targets for immunotherapeutic strategies in lymphoma. We report on the rationale for and initial efforts in the development of two unlabeled, humanized monoclonal antibodies directed against molecules commonly expressed in B-cell malignancies. hLL2 (epratuzumab; Immunomedics, Inc, Morris Plains, NJ) binds to the CD22 antigen, while Hu1D10 (apolizumab; Protein Design Labs, Inc, Fremont, CA) reacts with a polymorphism on the HLA-DR beta chain. Preclinical studies and early clinical evaluations suggest that these agents have a potential role as novel therapeutic targets for lymphoma with acceptable toxicity profiles. Further efforts will explore optimal clinical settings for their use, as well as define treatment regimens either as single agents or in combination with chemotherapy or other biologics. Semin Oncol 29 (suppl 2):81-86. Copyright © 2002 by W.B. Saunders Company.
PubMed: 28140096
DOI: 10.1053/sonc.2002.30149 -
Expert Opinion on Emerging Drugs Mar 2006Although the philosophy of management of patients with chronic lymphocytic leukaemia (CLL) has been altered with the advent of fludarabine-based therapies, impact on... (Review)
Review
Although the philosophy of management of patients with chronic lymphocytic leukaemia (CLL) has been altered with the advent of fludarabine-based therapies, impact on long-term survival is unclear and a significant proportion of patients will develop resistance to fludarabine. Similar to other haematological malignancies, a potential for 'cure' is likely to be achieved only if 'high-quality' complete remissions (CRs) are achieved. Treatment options for patients who develop resistance to fludarabine continue to be limited, with only a proportion obtaining a response (usually not CRs) with salvage therapies. This review summarises novel therapies that are being evaluated in patients with CLL, specifically those targeting the antiapoptotic Bcl-2 family of proteins and receptors (e.g., CD40, CD80, HLA-DR) involved in mediating survival signals from the microenvironment.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; B7-1 Antigen; Biphenyl Compounds; Clinical Trials as Topic; Drug Evaluation, Preclinical; HLA-DR Antigens; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Nitrophenols; Oligonucleotides, Antisense; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sialic Acid Binding Ig-like Lectin 2; Signal Transduction; Sulfonamides; Thionucleotides
PubMed: 16503834
DOI: 10.1517/14728214.11.1.167 -
Experimental Hematology Jul 2008Since the approval of rituximab in 1997, monoclonal antibodies have come to play an important role in the therapy of hematological malignancies. Rituximab, gemtuzumab... (Review)
Review
Since the approval of rituximab in 1997, monoclonal antibodies have come to play an important role in the therapy of hematological malignancies. Rituximab, gemtuzumab ozogamicin, and alemtuzumab are US Food and Drug Administration-approved for treatment of B-cell lymphomas, acute myeloid leukemia, and chronic lymphocytic leukemia, respectively. Multiple monoclonal antibodies directed against new and not-so-new cellular antigens are undergoing development and investigation all over the world. Most of these new compounds have undergone primatization or humanization, improving their specificity and decreasing their antigenicity when compared to earlier murine or chimeric products. This review will focus on three major aspects of monoclonal antibody therapy: 1) new therapeutic approaches with currently approved agents; 2) preclinical and clinical experience accumulated on new agents in the last few years; discussion will include available phase I, II, and III data on ofatumumab, epratuzumab, CMC-544, HeFi-1, SGN-30, MDX-060, HuM195 (lintuzumab), galiximab, lumiliximab, zanolimumab, and apolizumab; and 3) the role of naked and radiolabeled monoclonal antibodies in the hematopoietic stem cell transplantation setting.
Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Antigens, Neoplasm; Antineoplastic Agents; Clinical Trials as Topic; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Mice; United States; United States Food and Drug Administration
PubMed: 18565392
DOI: 10.1016/j.exphem.2008.04.018