Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Immunoconjugates”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 883 records · Page 49Linked to original sources
PubMed1997

Tumor uptake and metabolism of copper-67-labeled monoclonal antibody chCE7 in nude mice bearing neuroblastoma xenografts.

METHODS: ChCE7, an internalizing, neuroblastoma-specific monoclonal antibody (MAb), and its F(ab')2 fragments were derived with the bifunctional ligand 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl benzoic acid tetrahydrochloride (CPTA) and labeled with the potential therapeutic nuclide 67Cu. After internalization and degradation of these immunoconjugates in SKN-AS human neuroblastoma cells, the terminal degradation product was found to be the lysine adduct of the copper complex. In vivo distributions in nude mice bearing neuroblastoma xenografts were studied and extracts from tumor and tissue samples were analyzed. RESULTS: The intact MAb showed high tumor uptake, stable over 4 days postinjection (33.7% +/- 2.8% ID/g), with tumor/blood ratios increasing from 4.4 on Day 1 to 23.0 on Day 7 postinjection and low levels of radioactivity in other tissues. Analysis of tumor extracts by gel filtration chromatography and high-pressure liquid chromatography (HPLC) showed that over the period of 4 days radioactivity was present both in a high M(r) form, consisting of the MAb/antigen complex, as well as in a low M(r) form, consisting of the copper complex attached to short peptides, including the lys-CPTA complex. There was no evidence of aggregates or MAb/antigen complexes in the blood, radioactivity being exclusively in the form of intact MAb, and radioactivity in the liver was found to consist of intact MAb, MAb fragments and the lys-CPTA metabolite. In the case of the F(ab')2 fragments, high accumulation of radioactivity in the kidneys was observed and analysis of kidney extracts showed it to be due to rapid accumulation of the lys-CPTA complex. When kidney uptake and retention of the CPTA complex as well as of its lysine and glycine adducts was investigated, the lysine complex was taken up more strongly and retained longer in the kidneys than the other compounds. CONCLUSION: Copper-67-labeled MAb chCE7 F(ab')2 fragments were prepared using a novel bifunctional copper ligand 1-(p-aminobenzyl)-1,4,7,10-tetraazacyclodecane-4,7,10-triacetate (DO3A). Compared with MAb-chCE7 F(ab')2 fragments labeled by the CPTA ligand, labels using the DO3A ligand showed improved biodistributions resulting, 48 hr postinjection, in a 4-fold increase in tumor uptake and a 4-fold reduction of radioactivity in the kidneys.

Animals↗
PubMed1997

Exploration of novel strategies to enhance monoclonal antibodies targeting.

This paper highlights the major obstacles and prospects of antibody targeting for the radioimaging and therapy of human malignant lymphomas and more challenging solid tumors. To improve the therapeutic potential of monoclonal antibodies, we have focused our attention on the development of new and successful methods to augment antibody uptake in the tumor. These approaches include the use of radiolabeled streptavidin to target biotinylated monoclonal antibodies already bound to tumor, pretreatment with vasoactive immunoconjugates, and the use of chemically modified antibodies. Because of the promising preclinical data obtained with these three newer approaches, plans are underway to test them in the clinic. More generally, these approaches are applicable to the use of other monoclonal antibody/tumor systems for the diagnosis and therapy of human cancers and related diseases.

Antibodies, Monoclonal↗
PubMed1997

[Treatment of colorectal cancer with monoclonal antibodies].

This article reviews the treatment of colorectal carcinoma with monoclonal antibodies. Since the late seventies, several hundred patients with advanced disease have been treated with unconjugated antibodies, especially Mab 17-1A. The response rate of the studies has been less than 10%. In contrast, Mab given as adjuvant treatment for Duke's C colorectal carcinoma increased the five year survival with 30%. The actions of different types of immunoconjugates are reviewed.

Antibodies, Monoclonal↗
PubMed1997

Conjugation of the monoclonal antibody 17-1A with the nitroacridine compound C921 with the poly-L-lysine as an intermediate agent.

Monoclonal antibody 17-1A specific for human gastric carcinoma was coupled directly or indirectly, using poly-L-lysine as an intermediate, with nitroacridine compound C921. The aim of the study was to obtain selectively cytotoxic immunoconjugates for experimental therapy. Directly coupled conjugates retained antibody specificity towards cells of several human adenocarcinoma lines but were non cytotoxic in vitro, whereas conjugates obtained with the use of intermediate poly-L-lysine expressed only low, non-specific cytotoxicity, probably exerted by the poly-L-lysine content.

Acridines↗
PubMed1998

Prostate cancer abdominal metastases detected with indium-111 capromab pendetide.

To provide appropriate therapy for prostate cancer, accurate staging of the patient's disease is essential. Determination of tumor size, location, periprostatic extension and metastatic disease in the skeleton and soft tissue are needed to stage properly. Current diagnostic modalities may lead to understaging in 40%-70% of prostate cancer. Detection of metastatic disease, both at the time of initial diagnosis and in patients with suspected local recurrence, can significantly alter the type of therapy given. Clinical studies using the (111)In radiolabeled immunoconjugate, MAb 7E11-C5.3-GYK-DTPA (capromab pendetide), have shown the superiority of radioimmunoscintigraphy over other diagnostic modalities in the detection of both primary and metastatic prostate cancer. Radioimmunoscintigraphy with capromab pendetide depends on expression of tumor-associated antigen rather than lesion size. Earlier detection of extraprostatic invasion and metastases by means of radioimmunoscintigraphy provides valuable information for treatment decisions. A case of metastatic prostate cancer in the abdomen of a patient without local disease, in which the extent of disease was confirmed at autopsy after sudden cardiac arrest, is presented.

Abdominal Neoplasms↗
PubMed1998

Humanized M195 monoclonal antibody conjugated to recombinant gelonin: an anti-CD33 immunotoxin with antileukemic activity.

The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33pos cell lines HL60, OCI/AML2, and OCI/ AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33neg cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin. Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has antileukemic activity and should be considered for clinical testing in Phase I trials.

Antibodies, Monoclonal↗
PubMed1999

Pretreatment with a monoclonal antibody/interleukin-2 fusion protein directed against DNA enhances the delivery of therapeutic molecules to solid tumors.

The efficacy of molecular therapies for human malignancies is limited by inadequate accumulation within solid tumors. Our laboratory has developed a novel approach that uses monoclonal antibodies (MAbs) to direct vasoactive proteins to tumor sites to increase local vascular permeability and, in turn, improve the delivery of therapeutic reagents. Previously, we demonstrated that pretreatment with immunoconjugates containing interleukin-2 (IL-2) enhances specific tumor uptake of radiolabeled MAbs without affecting normal tissues. In the present study, we describe a fusion protein consisting of a chimeric antinuclear antibody and IL-2 (chTNT-3/IL-2) and illustrate its potential for improving the delivery of both MAbs and drugs. The ability of pretreatment with chTNT-3/IL-2 to increase specific tumor uptake of the MAb B72.3 was demonstrated in LS174T colon tumor-bearing mice. Tumor accretion of B72.3 increased nearly 3-fold, with no changes in normal tissues. Abrogation of this effect with N(G)-methyl-1-arginine, a chemical inhibitor of nitric oxide synthase, suggests that rapid generation of nitric oxide in the tumor is responsible for the enhanced uptake. To demonstrate that pretreatment with chTNT-3/IL-2 can improve the uptake of other clinically relevant MAbs in different tumor models, additional studies were performed in both lung and prostate xenograft models. Pretreatment with the fusion protein increased specific tumor uptake of the MAb NR-LU-10 in A427 lung tumor-bearing mice and enhanced tumor uptake of the MAb CYT-351 in LNCaP prostate tumor-bearing mice, 2.1-fold and 1.7-fold, respectively. Finally, tumor uptake of the radiolabeled thymidine analogue 125IUdR also increased approximately 3-fold after pretreatment, indicating that this approach can be extended to small molecules such as chemotherapeutic drugs. Because TNT-3 recognizes a universal nuclear antigen accessible in degenerating and necrotic cells within all solid tumors, this strategy may be applicable to the majority of human cancers.

Animals↗
PubMed1999

Purification, characterization and molecular cloning of trichoanguin, a novel type I ribosome-inactivating protein from the seeds of Trichosanthes anguina.

The seeds of the plant Trichosanthes anguina contain a type I ribosome-inactivating protein (RIP), designated trichoanguin, which was purified to apparent homogeneity by the combined use of ion-exchange chromatographies, i.e. first with DE-52 cellulose and then with CM-52 cellulose. The protein was found to be a glycoprotein with a molecular mass of 35 kDa and a pI of 9.1. It strongly inhibits the protein synthesis of rabbit reticulocyte lysate, with an IC50 of 0.08 nM, but only weakly that of HeLa cells, with an IC50 of 6 microM. Trichoanguin cleaves at the A4324 site of rat 28 S rRNA by its N-glycosidase activity. The cDNA of trichoanguin consists of 1039 nt and encodes an open reading frame coding for a polypeptide of 294 amino acid residues. The first 19 residues of this polypeptide encode a signal peptide sequence and the last 30 residues comprise an extension at its C-terminus. There are four potential glycosylation sites, located at Asn-51, Asn-65, Asn-201 and Asn-226. A comparison of the amino acid sequence of trichoanguin with those of RIPs such as trichosanthin, alpha-momorcharin, ricin A-chain and abrin A-chain reveals 55%, 48%, 36% and 34% identity respectively. Molecular homology modelling of trichoanguin indicates that its tertiary structure closely resembles those of trichosanthin and alpha-momorcharin. The large structural similarities might account for their common biological effects such as an abortifacient, an anti-tumour agent and anti-HIV-1 activities. Trichoanguin contains two cysteine residues, Cys-32 and Cys-155, with the former being likely to be located on the protein surface, which is directly amenable for conjugation with antibodies to form immunoconjugates. It is therefore conceivable that trichoanguin might be a better type I RIP than any other so far examined for the preparation of immunotoxins, with a great potential for application as an effective chemotherapeutic agent for the treatment of cancer.

Amino Acid Sequence↗
PubMed2025

Trastuzumab Deruxtecan for ERBB2-Mutant Metastatic Non-Small Cell Lung Cancer With or Without Brain Metastases: A Secondary Analysis of Randomized Clinical Trials.

IMPORTANCE: Brain metastases reduce overall survival rates of patients with non-small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC. OBJECTIVE: To assess the clinical effectiveness and safety of T-DXd 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases. DESIGN, SETTING, AND PARTICIPANTS: This post hoc secondary analysis pooled patients from the DESTINY-Lung01 (data cutoff date: December 3, 2021) and DESTINY-Lung02 (data cutoff date: December 23, 2022) clinical trials by T-DXd dose (5.4 mg/kg and 6.4 mg/kg). DESTINY-Lung01 was a multicenter, open-label, 2-cohort, nonrandomized phase 2 study, while DESTINY-Lung02 was a dose-blinded, multicenter, 2-cohort, randomized phase 2 study. Participants had a previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases at baseline. All statistical analyses were performed from April 2023 to October 2024. INTERVENTION: Patients received a T-DXd dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every 3 weeks. MAIN OUTCOME AND MEASURE: Systemic and intracranial effectiveness by blinded independent central review using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, sites of progression, and safety. RESULTS: This analysis included 102 patients in the T-DXd 5.4-mg/kg dose group (65 females [64%]; median [range] age, 57.5 [37.0-83.0] years and 59.5 [30.0-79.0] years in patients with and without brain metastases, respectively) and 141 patients in the T-DXd 6.4-mg/kg dose group (94 females [67%]; median [range] age, 62.5 [29.0-88.0] years and 59.0 [27.0-83.0] years in patients with and without brain metastases, respectively). In each group, 31% (32 of 102) and 38% (54 of 141) of patients, respectively, had baseline brain metastases and 53% (17 of 32) and 44% (24 of 54), respectively, received prior brain metastasis treatment. In patients with and without brain metastases, systemic confirmed objective response rates (ORRs) were 47% (15 of 32; 95% CI, 29%-65%) and 50% (35 of 70; 95% CI, 38%-62%), respectively, with the T-DXd 5.4-mg/kg dose, and 50% (27 of 54; 95% CI, 36%-64%) and 59% (51 of 87; 95% CI, 48%-69%) with the T-DXd 6.4-mg/kg dose. Median progression-free survival was 7.1 (95% CI, 5.5-9.7) months in the T-DXd 5.4-mg/kg dose group and 7.1 (95% CI, 4.5-9.6) months in the T-DXd 6.4-mg/kg dose group of patients with baseline brain metastases. Among patients with measurable baseline brain metastases, intracranial confirmed ORRs were 50% (7 of 14; 95% CI, 23%-77%) with the T-DXd 5.4-mg/kg dose and 30% (9 of 30; 95% CI, 15%-49%) with the T-DXd 6.4-mg/kg dose. At both doses, the safety profile of T-DXd was generally manageable, regardless of baseline brain metastases, favoring the T-DXd 5.4 mg/kg dose. CONCLUSIONS AND RELEVANCE: In this secondary analysis, T-DXd at the approved dose of 5.4 mg/kg showed antitumor activity in patients with previously treated ERBB2-mutant metastatic NSCLC with or without brain metastases. This finding supports T-DXd 5.4 mg/kg use in this population.

Adult↗
PubMed1996

Applicability of monoclonal antibody Fab fragments as a carrier of neocarzinostatin in targeting chemotherapy.

Two types of fragments of MAb A7 were produced to improve the efficacy and safety in targeting chemotherapy with neocarzinostatin. In this study, 125I-labeled F(ab')2 and Fab fragments of MAb A7 and 125I-labeled MAb A7 were injected intravenously into mice with pancreatic carcinoma xenografts, and the accumulation of each antibody in the tumors was compared. A greater amount of the 125I-labeled Fab fragments of MAb A7 localized in the tumor 2 h following the injection than was observed with the other probes. Relatively less 125I-labeled MAb A7 localized in the tumor 2 h following the injection than was observed with the other two probes. Moreover, reaction of rabbit antimouse IgC with the Fc portion, which is the most immunopotent region of the Fab and F(ab')2 fragments of MAb A7 and MAb A7, was determined by ELISA; the weakest reaction was observed with the Fab fragments of MAb A7. These results suggest that the Fab fragments of MAb A7 may be more suitable carriers of an anticancer drug that is inactivated rapidly in the blood, such as NCS, in targeting chemotherapy than either intact MAb A7 or the F(ab')2 fragments of MAb A7.

Animals↗
PubMed1997

In vivo expression of the CTLA4 inhibitory receptor in malignant and reactive cells from human lymphomas.

The CTLA4 receptor is a CD28 homologue which induces inhibitory effect on activated T-cells. Peripheral T-cells proliferate spontaneously in CTLA4-deficient mice. These results led to an analysis of CTLA4 expression in human lymphomas (n = 82) including Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHLs), using immunohistochemistry. CTLA4 was present in neoplastic cells from most (10/11) T-cell malignancies, except for anaplastic and lymphoblastic subtypes (0/4). Malignant B-cells from rare (3/55) B-NHLs (all of follicular subtype) were also CTLA4-positive. Other B-NHLs (52/55) were negative in malignant B-cells and occasionally positive in T-cells. Reactive small lymphocytes, but not Reed-Sternberg cells, from all (12/12) HD cases were strongly CTLA4-positive. The CTLA4 ligands CD80 and CD86 were simultaneously expressed in most CTLA4-negative lymphoma cases. CTLA4 is thus expressed either in the reactive or in the malignant cell populations, depending on the lymphoma subtype. These results provide new insights leading towards therapeutic strategies based either on enhancement of anti-tumour immunity by CTLA4 blockade in reactive lymphocytes or on triggering of a CTLA4-mediated inhibitory pathway in lymphoma cells.

Abatacept↗
PubMed1999

Phase I/II trial of (131)I-MN-14F(ab)2 anti-carcinoembryonic antigen monoclonal antibody in the treatment of patients with metastatic medullary thyroid carcinoma.

BACKGROUND: Monoclonal antibodies (MAbs) against carcinoembryonic antigen (CEA) have been recognized as targeting agents for medullary thyroid carcinoma (MTC). This Phase I/II study was initiated to determine the safety, maximum tolerated dose (MTD), and therapeutic potential of (131)I-MN-14 F(ab)2 anti-CEA MAb for patients with metastatic MTC. METHODS: Fifteen patients were enrolled in this study. Dose escalation was based on estimates of radiation dose to the bone marrow, and the radioactive dose given was determined by a pretherapy diagnostic study in which 8 mCi (0.6-20 mg) of (131)I-MN-14 F(ab)2 was administered 1 week prior to therapy. RESULTS: Three patients received an initial dose of 140 centigray (cGy) to bone marrow, 11 received 180 cGy, and 1 received 220 cGy. Myelosuppression was the only significant treatment-related dose-limiting toxicity (DLT), and the MTD appeared to be 180 cGy to the bone marrow. Human antimouse antibodies (HAMA) developed in 8 patients 2-6 weeks after therapy. Seven patients had a median of 55% reduction of tumor markers. One patient showed a dramatic improvement in the mass effect on the airways caused by 3 tumor lesions in the neck, with a 45% reduction of overall tumor burden. The disease has continued to be radiologically stable in 11 of 12 assessable patients for periods ranging from 3+ to 26+ months. CONCLUSIONS: Therapy with (131)I-MN-14 F(ab)2 is well tolerated and shows evidence of biochemical and radiologic antitumor activity. HAMA development suggests that humanized MAbs will be required in trials with repeated dose schedules. Further dose escalation, alone or in combination with other therapy modalities, is indicated for future trials, preferably with humanized anti-CEA MAbs.

Adult↗
PubMed1996

T-Cell co-stimulation by the CD28 ligand B7 is involved in the immune response leading to rejection of a spontaneously regressive tumor.

Cell variants from experimental tumors may lose their tumorigenicity or give rise to tumors that regress after a short period of progression in immunocompetent syngeneic animals. Rejection of these tumor cells is often T-cell-dependent. It has recently been reported that, besides the specific signal delivered through the clonogenic receptor, T-cell activation requires a co-stimulatory signal, delivered through its CD28 receptor by B7-1 and/or B7-2 molecules expressed at the surface of the antigen-presenting cells. CTLA4Ig, a fusion molecule that specifically inhibits B7-1 and B7-2 binding to their receptors of T cells, was used to investigate the role of B7 in the spontaneous regression of the tumors induced in syngeneic rats by REGb cells, a regressor cell line established from a chemically induced colon carcinoma. When rats received either 1 or 3 CTLA4Ig injections, REGb tumors grew 3 or 7 times larger than in control animals, respectively. However, in most animals, single or repeated CTLA4Ig injections delayed rather than suppressed REGb tumor rejection. Antibodies to CTLA4Ig appeared in treated rats and could explain this transient effect. Neither REGb cells nor freshly isolated MHC class-II+ antigen-presenting cells infiltrating REGb tumors expressed B7, establishing that the target of CTLA4Ig was not located inside the tumor. In contrast, MHC class-II+ B7+ accessory cells were found in the tissue, rather than the tumor itself, was the site of tumor-antigen presentation to tumor-specific T cells. These results establish the role of B7/CD28 co-stimulation pathway in the control of a spontaneously regressive tumor.

Abatacept↗
PubMed1997

Radioimmunotherapy of experimental pancreatic cancer with 131I-labeled monoclonal antibody PAM4.

We examined the therapeutic efficacy of 131I-labeled murine monoclonal antibody (MAb) PAM4 against human pancreatic cancers carried as xenografts in athymic nude mice. Animals bearing the CaPan1 tumor (0.2 cm3) were either untreated or were given, 131I-labeled nonspecific Ag8 antibody. By week 7 mean tumor size had grown 16.5 +/- 8.4-fold and 4.2 +/- 2.5-fold for the untreated and 131I-Ag8-treated animals, respectively. In contrast, animals administered 131I-PAM4 exhibited marked regression of tumors to an average of 15% of initial tumor volume. Since most pancreatic cancer patients present with large tumor burdens, the limitation of 131I-PAM4 treatment with respect to initial tumor size was investigated in animals bearing tumors of approximately 0.5 cm3, 1.0 cm3 and 2.0 cm3. Significant extension of survival time (>3-fold increase) was noted for both the 0.5 cm3 and 1.0 cm3 131I-PAM4-treated groups, compared to their respective untreated controls. Even in the group bearing large 2.0-cm3 tumors, survival was increased 2-fold over the control group. To further improve anti-tumor effects in large tumors, 2 injections of 131I-PAM4 were administered at a 4-week interval to animals bearing tumors of approximately 1.0 cm3. Significant extended survival was noted for the group receiving 2 doses when compared to the group receiving only 1 dose.

Adenocarcinoma↗
PubMed1998

Human Trop-2 is a tumor-associated calcium signal transducer.

Trop-2/EGP-1/GA733-1 is a recently identified cell surface glycoprotein highly expressed by human carcinomas. The cytoplasmic tail of Trop-2 possesses potential serine and tyrosine phosphorylation sites and a phosphatidyl-inositol binding consensus sequence. Thus, we investigated whether Trop-2 might be a functional signaling molecule. Using the fluorescent probe Fura-2, we assayed the cytoplasmic calcium levels in human cancer cells stimulated with anti-Trop-2 or control antibodies. Three anti-Trop-2 MAbs, Rs7-7G11, MOv16 and 162-46.2 specifically induced a transient intracellular calcium level increment in up to 40% of the experiments performed. Polyclonal antisera recognizing recombinant Trop-2 molecules possessed a much lower stimulation efficiency. The average latency of antibody-induced Ca2+ rise for OvCa-432 cells was 64+/-26 sec. Internal Ca2+ concentrations reached peaks of 190+/-24 nM vs. basal levels of 61+/-4 nM and returned to baseline within 193+/-37 sec. Similar values were obtained in MCF-7 cells. For comparison, stimulation of P2-purinergic receptors on MCF-7 and OvCa-432 cells induced a Ca2+ rise in most cases, leading to average internal Ca2+ concentrations of 297+/-41 and 391+/-39 nM, respectively. Our findings show that Trop-2 transduces an intracellular calcium signal, are consistent with the hypothesis that it acts as a cell surface receptor and support a search for a physiological ligand.

Adenosine Triphosphate↗
PubMed1998

Targeting T cells against brain tumors with a bispecific ligand-antibody conjugate.

High-affinity receptors expressed on the surface of some tumors can be exploited by chemically conjugating the ligand for the receptor and an antibody against immune effector cells, thus redirecting their cytolytic potential against the tumor. Ovarian carcinomas and some brain tumors express the high-affinity folate receptor (FR). In this report, a transgenic mouse model that generates endogenously arising choroid plexus tumors was used to show that folate/anti-T-cell receptor antibody conjugates can direct infiltration of T cells into solid brain tumor masses. An engineered single-chain Fv form of the anti-T-cell receptor antibody KJ16 was conjugated with folate, to produce a bispecific agent that was substantially smaller than most previously characterized bispecific antibodies. Folate conjugation to the antibody increased T-cell infiltration into the tumors by 10- to 20-fold, and significantly prolonged survival of the mice.

Animals↗
PubMed1998

Intracerebral bispecific ligand-antibody conjugate increases survival of animals bearing endogenously arising brain tumors.

Bispecific antibodies capable of simultaneously binding a tumor surface antigen and the T-cell receptor/CD3 complex are capable of inducing polyclonal immune effector cells to destroy targeted tumor cells. Bispecific antibody immunotherapies have shown some promise against tumors of hematopoietic origin such as lymphomas, but use of bispecific antibodies for the treatment of solid tumors has been less fully explored. To test the preclinical potential of bispecific antibody therapy against an endogenously arising solid brain tumor, we have utilized a novel variation of conventional bispecific antibodies, referred to as bispecific ligand-antibody conjugates, to target choroid plexus tumors. The bispecific ligand-antibody conjugate described in this study is a chemical conjugate between an anti-CD3 monoclonal antibody (MAb) and folic acid, the ligand for a high-affinity surface receptor expressed on the surface of choroid plexus tumors. SV11 mice transgenic for SV40 large T antigen and its promoter develop solid choroid plexus tumors in the brain. We demonstrate that choroid plexus tumor cells are susceptible in vitro to cytolysis mediated by cytotoxic T cells in the presence of the bispecific ligand-antibody conjugate in a folate-inhibitable manner. Adoptive immunotherapy studies demonstrate the potential benefits of the bispecific ligand-antibody conjugate in vivo. The bispecific conjugate is capable of retaining adoptively transferred T lymphocytes specifically within tumor tissue for periods of up to at least 1 week. Further, following intracerebro-ventricular injection of bispecific conjugate and splenocytes containing activated cytotoxic T cells, T cells were observed to penetrate to interior regions of the tumor. A single treatment of adoptively delivered activated effectors and bispecific conjugate into the brain ventricles was insufficient to produce significant increases in survival of SV11 mice, but repeated treatment through indwelling cannulas prolonged survival of animals treated with activated effectors and bispecific ligand-antibody conjugate compared to animals treated with activated effectors or saline alone. Our results demonstrate that the SV11 model may be useful for preclinical evaluation and optimization of bispecific ligand-antibody conjugate treatments of solid tumors.

Animals↗