Phase I Trial of Yttrium-90—Labeled Anti—Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Androgen-Independent Prostate Cancer

Milowsky, Matthew I.; Nanus, David M.; Kostakoğlu, Lale; Vallabhajosula, Shankar; Goldsmith, Stanley J.; Bander, Neil H.

doi:10.1200/jco.2004.09.154

Cited by 283 publications

(213 citation statements)

References 18 publications

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“…PSMA, also known as glutamate carboxypeptidase II or N-acetyl-L-aspartyl-L-glutamate peptidase I, is an excellent cell-surface target for prostate cancer because its expression is up-regulated throughout all stages of prostate cancer progression and is highly restricted to prostate cells, with very low levels of expression detectable in other tissues (19). Indeed, several αPSMA monoclonal antibodies have been used as vehicles for the targeted delivery of cytotoxic agents including radioactive isotopes, small molecules, and protein toxins (4,20,21). A series of small molecule PSMA inhibitors with high affinity (in the low nanomolar range) and selectivity also have been explored for selective lysis or imaging of PSMA + prostate cancer cells (18,22,23).…”

Section: Resultsmentioning

confidence: 99%

Bispecific small molecule–antibody conjugate targeting prostate cancer

Kim

Axup

Lawson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Bispecific antibodies, which simultaneously target CD3 on T cells and tumor-associated antigens to recruit cytotoxic T cells to cancer cells, are a promising new approach to the treatment of hormone-refractory prostate cancer. Here we report a site-specific, semisynthetic method for the production of bispecific antibodylike therapeutics in which a derivative of the prostate-specific membrane antigen-binding small molecule DUPA was selectively conjugated to a mutant αCD3 Fab containing the unnatural amino acid, p-acetylphenylalanine, at a defined site. Homogeneous conjugates were generated in excellent yields and had good solubility. The efficacy of the conjugate was optimized by modifying the linker structure, relative binding orientation, and stoichiometry of the ligand. The optimized conjugate showed potent and selective in vitro activity (EC 50 ∼100 pM), good serum half-life, and potent in vivo activity in prophylactic and treatment xenograft mouse models. This semisynthetic approach is likely to be applicable to the generation of additional bispecific agents using drug-like ligands selective for other cell-surface receptors.antibody engineering | immunotherapy

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Section: Resultsmentioning

confidence: 99%

Bispecific small molecule–antibody conjugate targeting prostate cancer

Kim

Axup

Lawson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The details of this technique have been published in previous studies using J591 and may be found there (11).…”

Section: End Pointsmentioning

confidence: 99%

“…Previously published phase I studies of J591 have dose escalated the radioconjugate and have examined the safety and antitumor effects of increasing amounts of radiation (10,11). To develop J591 as a naked antibody, radioconjugate, or chemoconjugate, we sought to explore the effect of dose escalating the antibody mass on pharmacokinetics, biodistribution, and ADCC activation, the putative mechanism by which unlabeled antibody would mediate antitumor effects.…”

mentioning

confidence: 99%

Pilot Trial of Unlabeled and Indium-111–Labeled Anti–Prostate-Specific Membrane Antigen Antibody J591 for Castrate Metastatic Prostate Cancer

Morris

Divgi

Pandit‐Taskar³

et al. 2005

Clinical Cancer Research

110

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Background: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591has not been explored. Patients and Methods: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, NV ,N 00 ,N 000 -tetraacetic acid, were labeled with 5 mCi indium-111 ( 111 In) as a tracer. One group of patients received unlabeled J591before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed. Results: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591was comparable in both groups. The meanT 1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline.Conclusions: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591as a radioconjugate are under way.

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“…[8][9][10][11] Biochemical and objective measurable disease responses were reported in some patients treated with radionuclide conjugates of a humanized MAb, J591, that binds to the extracellular domain of PSMA. [12][13][14][15][16][17][18] The safety profile of passive immunotherapy with J591 and its derivatives, along with specific localization of radionuclide-labeled MAb to tumor sites in patients with metastatic prostate cancer or other solid tumors, supports the potential clinical benefit of antibodies and T cells specific for PSMA induced by active immunization. In addition to these studies, clinical trials of active immunotherapy have been completed with no evidence of toxicity, [19][20][21][22] and some anecdotal declines in serum prostate-serum antigen (PSA) were reported.…”

mentioning

confidence: 99%

Induction of autoantibodies to syngeneic prostate‐specific membrane antigen by xenogeneic vaccination

Gregor

Wolchok

Turaga

et al. 2005

Intl Journal of Cancer

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Prostate-specific membrane antigen (PSMA) is a prototypical differentiation antigen expressed on normal and neoplastic prostate epithelial cells, and on the neovasculature of many solid tumors. Monoclonal antibodies specific for PSMA are in development as therapeutic agents. Methodologies to actively immunize against PSMA may be limited by immunologic ignorance and/or tolerance that restrict the response to self-antigens. Our studies have previously shown that xenogeneic immunization with DNA vaccines encoding melanosomal differentiation antigens induces immunity in a mouse melanoma model. Here we apply this approach to PSMA to establish proof of principle in a mouse model. Immunization with xenogeneic human PSMA protein or DNA induced antibodies to both human and mouse PSMA in mice. Monoclonal antibodies specific for mouse PSMA were generated to analyze antibody isotypes and specificity for native and denatured PSMA at the clonal level. Most antibodies recognized denatured PSMA, but C57BL/6 mice immunized with xenogeneic PSMA DNA followed by a final boost with xenogeneic PSMA protein yielded autoantibodies that reacted with native folded mouse PSMA. Monoclonal antibodies were used to confirm the expression of PSMA protein in normal mouse kidney. These results establish the basis for clinical trials to test PSMA DNA vaccines in patients with solid tumors that either express PSMA directly or that depend on normal endothelial cells expressing PSMA for their continued growth. ' 2005 Wiley-Liss, Inc.

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Phase I Trial of Yttrium-90—Labeled Anti—Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Androgen-Independent Prostate Cancer

Abstract: The recommended dose for (90)Y-J591 is 17.5 mCi/m(2). Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of (90)Y-J591 in the treatment of patients with PC.

Cited by 283 publications

References 18 publications

Bispecific small molecule–antibody conjugate targeting prostate cancer

Bispecific small molecule–antibody conjugate targeting prostate cancer

Pilot Trial of Unlabeled and Indium-111–Labeled Anti–Prostate-Specific Membrane Antigen Antibody J591 for Castrate Metastatic Prostate Cancer

Induction of autoantibodies to syngeneic prostate‐specific membrane antigen by xenogeneic vaccination

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