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Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is 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...
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Citations
... Storing conditions of the drug like if stored in abnormal conditions then oxidation, reduction, methylation or related damage to the protein can result inimmunogenicity (Cleland and others [16]; Morris and others [17]; Wakankar and Borchardt [18]). Potential cytokines, their immunogenic factor and subsequent responses are tabulated in Table 1. ...
... The deimmunized antibodies specific for prostrate membrane antigen have passed different stages of clinical trials and are approved for clinical use. In clinical trials, these antibodies are conjugated with a radioactive probe and do not show antitherapeutic immune responses [92][93][94][95]. So, T cell epitopes are one of the crucial factors taken into consideration to control antitherapeutic antibody responses. ...
Regarded as highly successful in their clinical applications, therapeutic proteins are now widely applied for the precise treatment of several diseases. Common forms of therapeutic proteins include enzymes, antibodies, and recombinant proteins. Here, we discuss different aspects of the clinical applications of protein-based therapeutics, including therapeutic proteins, their mechanisms and metabolism, challenges, precision medicine, and computer-aided drug designing. In addition, an overview of recently approved therapeutic proteins is provided. Conclusively, this chapter delivers comprehensive information on clinical applications of protein-based therapeutics, emerging trends, and challenges.
... Next, AgeI/EcoRV-flanked cassettes encoding the scFv/partial CD8a hinge cassette corresponding to the CD20-specific antibodies, 1F5, Leu16, and 2F2, were similarly obtained by gene synthesis and pasted into the Kymriah CAR construct to substitute the FMC63-based antigen-binding module. J591-derived PSMA-specific scFv was cloned by PCR from a previously published construct [54][55][56] to obtain an irrelevant PSMA-specific CAR of an identical structural format. Therefore, all of the CAR constructs obtained had a well-described hinge, a transmembrane region derived from that of the human CD8a, and a second generation co-stimulation/signaling cassette encoding the fusion of the intracellular region of human 4-1BB and CD3ζ [57,58]. ...
Over the past decade, CAR T cell therapy for patients with B cell malignancies has evolved from an experimental technique to a clinically feasible option. To date, four CAR T cell products specific for a B cell surface marker, CD19, have been approved by the FDA. Despite the spectacular rates of complete remission in r/r ALL and NHL patients, a significant proportion of patients still relapse, frequently with the CD19 low/negative tumor phenotype. To address this issue, additional B cell surface molecules such as CD20 were proposed as targets for CAR T cells. Here, we performed a side-by-side comparison of the activity of CD20-specific CAR T cells based on the antigen-recognition modules derived from the murine antibodies, 1F5 and Leu16, and from the human antibody, 2F2. Whereas CD20-specific CAR T cells differed from CD19-specific CAR T cells in terms of subpopulation composition and cytokine secretion, they displayed similar in vitro and in vivo potency.
... Morris et al. have shown in a phase I pilot study on 40 patients with mCRPC that 111 In-J591 is welltolerated, with the optimal dosages being 25 mg for radioimmunotherapy and 100 mg for immunotherapy [37]. 225 ...
Purpose of review:
Targeting Prostate-Specific Membrane Antigen (PSMA) has paved the way for personalized medicine in prostate cancer (PCa) patients. This review aims to highlight the role of PSMA targeting antibodies in PCa, for diagnostic and therapeutic purposes.
Recent findings:
PSMA Positron Emission Tomography/Computed Tomography has been a game changer in the diagnosis of PCa in the recent decade. Two anti-PSMA monoclonal antibodies have been studied in PCa: 7E11-C35 (limited use) and J591. J591 antibody was used for diagnostic purposes coupled with different radionuclides. Most importantly, it was combined to numerous therapeutic radionuclides such as Lutetium-177 (177Lu), Yttrium-90 (90Y), Indium-111 (111In), and Actinium-225 (225Ac). It was also conjugated to drugs forming antibody-drug conjugates (e.g. MLN2704 and PSMA-ADC). These compounds were tested in recent phase I/II clinical trials.
Summary:
PSMA targeting antibodies are very promising for further clinical investigation and continue to be a momentous research area, for both imaging and therapeutic settings. Although some clinical trials resulted in unfavorably safety profiles for some antibodies, they validated PSMA as a crucial immunoconjugate target.
... They further outlined that a dose of 100 mg was optimal if the intent was for immunotherapy, but optimal antibody mass seems to be 25 mg when used for the purpose of targeted radiotherapy. 102 In a similar study, Yttrium-90-labeled J591[(90) Y-J591] was used in men with CRPC. Only 2 of the 29 patients in this study experienced objective measurable disease response, which was reflected by a >50% fall in PSA levels, which lasted for about 8 months, whereas 6 patients (21%) were reported to have stable PSA levels. ...
... 103 Both the previously mentioned trials showed successful targeting of skeletal and soft tissue metastatic disease in most patients. 102,103 Further, this evidence was supported by a phase II study by Tagawa MLN591 antibody using a thiopentanoate link that contains disulfide bonds; however, these disulfide linker bonds are particularly labile, resulting in deconjugation of the bond and release of DM1 in the plasma itself rather than the targeted cancer cell, leading to considerable toxicity. This can be overcome by using immunoconjugates compounded with a less labile thioether linker. ...
Metastatic castrate resistant prostate cancer (PCa) remains an incurable entity. In the era of immunotherapy, the complex PCa microenvironment poses a unique challenge to the successful application of this class of agents. However, in the last decade, a tremendous effort has been made to explore this field of therapeutics. In this review, the physiology of the cancer immunity cycle is highlighted in the context of the prostate tumor microenvironment, and the current evidence for use of various classes of immunotherapy agents including vaccines (dendritic cell based, viral vector based and DNA/mRNA based), immune checkpoint inhibitors, Chimeric antigen receptor T cell therapy, antibody-mediated radioimmunotherapy, antibody drug conjugates, and bispecific antibodies, is consolidated. Finally, the future directions for combinatorial approaches to combat PCa are discussed.
... A substantial improvement in PSMA imaging was achieved with the generation of J591, a humanized antibody targeting an epitope on the extracellular region of PSMA. J591 has been labeled with radionuclides for both PET and SPECT imaging of PCa lesions in humans (34)(35)(36). However, as antibody and antibody-fragment derived agents require administration of the radiolabeled agent several days before effective PSMA/tumor imaging can be performed, as this time is required for clearance of the tracer and optimal tumor/background signal. ...
Metastatic prostate cancer is incurable, and novel methods to detect the disease earlier and to direct definitive treatment are needed. Molecularly specific tools to localize diagnostic and cytotoxic radionuclide payloads to cancer cells and the surrounding microenvironment are recognized as a critical component of new approaches to combat this disease. The implementation of theranostic approaches to characterize and personalize patient management is beginning to be realized for prostate cancer patients. This review article summarized clinically translated approaches to detect, characterize, and treat disease in this rapidly expanding field.
... Therefore, it failed to gain wide acceptance in the field of nuclear medicine. Subsequently, a humanized monoclonal antibody (J591) to target the extracellular domain of the PSMA was evaluated preclinically as an imaging and radioimmunotherapeutic agent [13][14][15][16]. Despite improved target efficiency, its slow pharmacokinetics and slow clearance from non-target tissue made it incompatible for diagnostic applications. ...
: Prostate-specific membrane antigen (PSMA) is a biomarker expressed on the surface of prostate cancer (PCa). In an effort to improve the detection and treatment of PCa, small urea-based PSMA inhibitors have been studied extensively. In the present study, we aimed to develop 99mTc-tricabonyl labeled urea-based PSMA conjugates containing isonitrile (CN-R)-coordinating ligands ([99mTc]Tc-15 and [99mTc]Tc-16). Both the PSMA conjugates were obtained at high radiochemical efficiency (≥98.5%). High in vitro binding affinity was observed for [99mTc]Tc-15 and [99mTc]Tc-16 (Kd = 5.5 and 0.2 nM, respectively) in PSMA-expressing 22Rv1 cells. Tumor xenografts were conducted using 22Rv1 cells and rapid accumulation of [99mTc]Tc-16 (1.87 ± 0.11% ID/g) was observed at 1 h post-injection, which subsequently increased to (2.83 ± 0.26% ID/g) at 4 h post-injection. However, [99mTc]Tc-15 showed moderate tumor uptake (1.48 ± 0.18% ID/g), which decreased at 4 h post-injection (0.81 ± 0.09% ID/g). [99mTc]Tc-16 was excreted from non-targeted tissues with high tumor-to-blood (17:1) and tumor-to-muscle ratio (41:1) at 4 h post-injection at approximately 4 times higher levels than [99mTc]Tc-15. Uptakes of [99mTc]Tc-15 and [99mTc]Tc-16 to PSMA-expressing tumor and tissues were significantly blocked by co-injection of 2-(Phosphonomethyl)-pentandioic acid (2-PMPA), suggesting that their uptakes are mediated by PSMA specifically. Whole-body single photon emission computed tomography imaging of [99mTc]Tc-16 verified the ex vivo biodistribution results and demonstrated clear visualization of tumors and tissues expressing PSMA compared to [99mTc]Tc-15. In conclusion, using [99mTc]Tc-16 rather than [99mTc]Tc-15 may be the preferable because of its relatively high tumor uptake and retention.
... An initial approach to targeting PSMA was successfully realized using the humanized monoclonal antibody J591 [2], which has been labeled with 89 Zr [3], 90 Y [4], 111 In [5], 177 Lu [4], and 213 Bi [6], and undergone preclinical and clinical evaluation. Subsequently, a number of small molecule PSMA inhibitors for imaging [7][8][9][10][11][12][13][14][15] and/or therapy [16][17][18][19] of prostate cancer have been described, and a smaller number of these have entered clinical evaluation [20][21][22][23][24][25][26][27][28][29]. ...
... The antitumor effect of these antibodies is still under evaluation, and some did not show expected efficacy. For example, in a pilot trial of radio-labeled humanized J591 for the treatment of castrate metastatic prostate cancer, only 1 in 14 patients had a >50% decline in PSA level (21). Thus, more human PSMA antibodies with high binding affinity or therapeutic efficacy are still needed. ...
Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related death. It is of vital importance to develop new strategies for prostate cancer therapy. PSMA (prostate-specific membrane antigen) is specifically expressed in prostate cancer and the neovasculature of certain cancer types, thus is considered to be an ideal target for cancer therapy. In our previous study, we have obtained a PSMA-specific single-chain variable fragment (scFv), named gy1, from a large yeast display naïve human scFv library. In this study, we reconstructed the PSMA scFv into a fully human antibody (named PSMAb) and evaluated its characterization both in vitro and in vivo We showed that PSMAb can specifically bind with and internalize into PSMA+ cells. The binding affinity of PSMAb is measured to be at nanomolar level, and PSMAb has very good thermostability. In vivo study showed that near IR dye-labeled PSMAb can specifically localize at PSMA+ tumors, and the application of PSMAb in vivo significantly inhibited the growth of PSMA+ tumors, but not PSMA- tumors. At the studied doses, no obvious toxicity was observed when applied in vivo, as shown by the relative normal liver and kidney function and normal structure of important organs, shown by hematoxylin and eosin staining. In addition, PSMAb may inhibit tumor growth through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity mechanisms. Our results indicated that the novel fully human antibody, PSMAb, deserve further study for PSMA-targeted diagnosis and therapy for prostate cancer and other cancer types with vascular PSMA expression.
... 4,5 We have previously demonstrated that the anti-PSMA monoclonal antibody J591 can be radiolabeled and delivered in a single dose with efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC), but with dose-limiting myelosuppression. [6][7][8][9][10][11] Cancer August 1, 2019 ...
... [18][19][20] We showed the ability to target prostate cancer with radiolabeled J591 and demonstrated efficacy with a dose-response effect with 177 Lu-J591, with dose-limiting thrombocytopenia. [6][7][8]10,11 In this study, we report that a higher cumulative dose of 177 Lu can be delivered by dose fractionation with acceptable toxicity. Of note, dose fractionation is conceptually different than retreatment, aiming to deliver a higher cumulative amount of radiation in a single cycle without allowing for tumor repopulation between doses. ...
... In contrast to the high incidence of low-grade xerostomia in prospective studies of 177 Lu-targeted radioligand therapy, we have not observed this phenomenon (nor targeting of salivary glands by imaging). [6][7][8]10,11,24,28 Renal toxicity is a potential late side effect of PSMA radioligand therapy. 29 No long-term follow-up has been performed with PSMA-targeted radioligand therapy, but we have not observed any significant acute or delayed nephrotoxicity in our studies with many years of follow-up. ...
Background
Prostate cancer is radiosensitive. Prostate‐specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration‐resistant tumors. Lutetium‐177–labeled anti‐PSMA monoclonal antibody J591 (¹⁷⁷Lu‐J591) targets prostate cancer with efficacy and dose‐response/toxicity data when delivered as a single dose. Dose fractionation may allow higher doses to be administered safely.
Method
Men with metastatic castration‐resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose‐escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses of ¹⁷⁷Lu‐J591 2 weeks apart. ¹⁷⁷Lu‐J591 imaging was performed after treatment, but no selection for PSMA expression was performed before enrollment. Phase 2 patients had circulating tumor cell (CTC) counts assessed before and after treatment.
Results
Forty‐nine men received fractionated doses of ¹⁷⁷Lu‐J591 ranging from 20 to 45 mCi/m² ×2 two weeks apart. The dose‐limiting toxicity in phase 1 was neutropenia. The RP2Ds were 40 mCi/m² and 45 mCi/m² ×2. At the highest RP2D (45 mCi/m² ×2), 35.3% of patients had reversible grade 4 neutropenia, and 58.8% of patients had thrombocytopenia. This dose showed a greater decrease in prostate‐specific antigen (PSA) levels and longer survival (87.5% with any PSA decrease, 58.8% with >30% decrease, 29.4% with >50% decrease; median survival, 42.3 months [95% confidence interval, 19.9‐64.7]). Fourteen of 17 (82%) patients with detectable CTCs experienced a decrease in CTC count. Overall, 79.6% of patients had positive PSMA imaging; those with less intense PSMA imaging tended to have poorer responses.
Conclusion
Fractionated administration of ¹⁷⁷Lu‐J591 allowed higher cumulative radiation dosing. The frequency and depth of PSA decrease, overall survival, and toxicity (dose‐limiting myelosuppression) increased with higher doses.
