Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas

Blood ◽  
2003 ◽  
Vol 101 (6) ◽  
pp. 2340-2348 ◽  
Author(s):  
John M. Pagel ◽  
Nathan Hedin ◽  
Krishnan Subbiah ◽  
Damon Meyer ◽  
Robert Mallet ◽  
...  
Keyword(s):  
Tumor Uptake ◽  
Tetraacetic Acid ◽  
Athymic Mice ◽  
Normal Organ ◽  
Non Hodgkin Lymphoma ◽  
Antibody Conjugate ◽  
Pretargeted Radioimmunotherapy ◽  
Anti Cd20 ◽  
Yttrium 90 ◽  
Cd20 Antibodies

Radiolabeled anti-CD20 antibodies produce responses in 60% to 95% of patients with relapsed non-Hodgkin lymphoma (NHL); however, absorbed radiation ratios between tumors and normal organs are relatively low, and many patients have relapses. In this study we compared the abilities of anti-CD45 (BC8) and anti-CD20 (1F5) antibodies to target human Ramos lymphoma xenografts in athymic mice. When direct radioiodination was performed with conventional methods, BC8 delivered 2- to 4-fold more radioiodine to tumors than 1F5, with tumor-to–normal organ ratios as high as 20:1 using radiolabeled BC8 compared with a maximal ratio of 9.8:1 using radioiodinated 1F5. To optimize the biodistribution of radioactivity, we performed studies following a pretargeting method using streptavidin (SA)–conjugated BC8 and 1F5. Injection of a synthetic clearing agent decreased the circulating level of conjugates by 80% to 90% within 1 hour. Pretargeting with BC8-SA resulted in a 2- to 4-fold greater tumor uptake of radiolabeled biotin than with 1F5-SA, with maximal tumor-to–normal organ ratios of more than 80:1 and approximately 16:1, respectively. Therapy experiments demonstrated that 400 μCi (14.8 MBq) or more of yttrium-90-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)–biotin cured 100% of mice treated with BC8-SA and more than 90% of mice pretargeted with 1F5-SA, with complete remission occurring 8 to 10 days sooner in mice receiving BC8-SA. After treatment with 200 μCi (7.4 MBq) 90Y-DOTA-biotin, 70% of the mice treated with BC8-SA were cured, but no mice were cured using 1F5-SA. Doses up to 800 μCi (29.6 MBq) 90Y-DOTA-biotin were delivered with minor toxicity using either antibody conjugate. These lymphoma xenograft data suggest that pretargeted radioimmunotherapy using either anti-CD20 or anti-CD45 conjugates is highly effective and minimally toxic.

scholarly journals Comparison of a tetravalent single-chain antibody-streptavidin fusion protein and an antibody-streptavidin chemical conjugate for pretargeted anti-CD20 radioimmunotherapy of B-cell lymphomas

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 328-336 ◽  
Author(s):  
John M. Pagel ◽  
Yukang Lin ◽  
Nathan Hedin ◽  
Anastasia Pantelias ◽  
Donald Axworthy ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Athymic Mice ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Normal Organ ◽  
Normal Tissues ◽  
Non Hodgkin Lymphoma ◽  
Chemical Conjugate ◽  
Anti Cd20 ◽  
Cd20 Antibodies

The efficacy of radioimmunotherapy (RIT) for patients with relapsed non-Hodgkin lymphoma (NHL) is limited by nonspecific delivery of radiation to normal tissues due to the long circulating half-life of radiolabeled anti-CD20 antibodies (Abs). Pretargeted RIT using a covalent conjugate of the 1F5 anti-CD20 Ab with streptavidin (SA) has been shown to augment the efficacy of RIT and decrease toxicity compared with a directly labeled 1F5 Ab. We have engineered a tetravalent singlechain 1F5 (scFv)4SA fusion protein and compared it to the 1F5-SA conjugate. Athymic mice bearing Ramos lymphoma xenografts received either the conjugate or fusion protein, followed 20 hours later by a biotin-N-acetyl-galactosamine clearing agent, followed 4 hours later by 111In-DOTA-biotin. After 24 hours, 11.4% ± 2.1% of the injected dose of radionuclide was present per gram of tumor (% ID/g) using 1F5 (scFv)4SA compared with 10.8% ± 2.5% ID/g with 1F5 Ab-SA. Superior tumor-to-normal organ ratios of radioactivity were consistently seen using the fusion protein compared with the chemical conjugate (eg, tumor-to-blood ratio > 65:1 after 48 hours with the fusion protein, but < 7:1 with the conjugate). More than 90% of lymphomabearing mice could be cured with minimal toxicity using either reagent followed by 1200 μCi (44.4 MBq) 90Y-DOTA-biotin. (Blood. 2006;108:328-336)

scholarly journals Comparative biodistributions of pretargeted radioimmunoconjugates targeting CD20, CD22, and DR molecules on human B-cell lymphomas

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4980-4987 ◽  
Author(s):  
Anastasia Pantelias ◽  
John M. Pagel ◽  
Nathan Hedin ◽  
Laura Saganic ◽  
Shani Wilbur ◽  
...  
Keyword(s):  
Antigen Expression ◽  
Target Antigen ◽  
Tumor Uptake ◽  
Normal Organ ◽  
Non Hodgkin Lymphoma ◽  
Hla Dr ◽  
Antigenic Expression ◽  
Anti Cd20 ◽  
Tumor Antigen Expression ◽  
Human B Cell

Abstract Pretargeted radioimmunotherapy (PRIT) using streptavidin (SA)–conjugated antibodies (Abs), followed by clearing agent and radiolabeled biotin is a promising method that can increase the effectiveness of RIT, while decreasing the toxicities associated with directly labeled Abs. Although CD20 has been the traditional target antigen for RIT of non-Hodgkin lymphoma (NHL), studies targeting HLA DR and CD22 have yielded promising results. Targeting all 3 antigens at once may further augment the effect of PRIT. This study compares the targeting of Ramos, Raji, and FL-18 lymphoma xenografts with either anti-CD20 Ab/SA (1F5/SA), anti-HLA DR Ab/SA (Lym-1/SA), anti-CD22 Ab/SA (HD39/SA), or all 3 conjugates in combination, followed 24 hours later by a biotin-N-acetyl-galactosamine clearing agent, and 3 hours after that by 111In-DOTA-biotin. The Ab/SA conjugate yielding the best tumor uptake and tumor-to–normal organ ratios of radioactivity varied depending on the target antigen expression on the cell line used, with 1F5/SA and Lym-1/SA yielding the most promising results overall. Also, the best tumor-to–normal organ ratios of absorbed radioactivity were obtained using single conjugates optimized for target tumor antigen expression rather than the combination therapy. This study highlights the importance of screening the antigenic expression on lymphomas to select the optimal reagent for PRIT.

scholarly journals CD20 antibodies: type II to tango?

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5061-5063 ◽  
Author(s):  
Marinus H. J. van Oers
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Type Ii ◽  
Non Hodgkin Lymphoma ◽  
Anti Cd20 ◽  
Intense Research ◽  
Cd20 Antibodies

Although the chimeric anti-CD20 monoclonal antibody (mAb) rituximab has revolutionized the treatment of B-cell non-Hodgkin lymphoma (NHL), still many patients relapse and an increasing number become refractory to rituximab-containing therapy. This has initiated intense research to develop more potent anti-CD20 antibodies.

Conventional and Pretargeted Radioimmunotherapy with Bismuth-213 to Target and Treat CD20-Expressing Non-Hodgkin Lymphoma: A Preclinical Model for Consolidation Therapy to Eradicate Minimal Residual Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2705-2705
Author(s):  
Steven I. Park ◽  
Jaideep Shenoi ◽  
John M. Pagel ◽  
Donald K. Hamlin ◽  
Nural Orgun ◽  
...  
Keyword(s):  
B Cell ◽  
Minimal Residual Disease ◽  
Median Survival ◽  
Half Life ◽  
Therapeutic Efficacy ◽  
Residual Disease ◽  
Tumor Uptake ◽  
Athymic Mice ◽  
Normal Organ ◽  
Minimal Residual

Abstract Abstract 2705 Poster Board II-681 Conventional radioimmunotherapy (RIT) with directly radiolabeled anti-B cell antibodies (Ab) induces remissions in 50 to 80% of patients with relapsed or refractory indolent non-Hodgkin lymphomas (NHL). Although administering RIT as consolidation after chemotherapy improves response rates and produces long-term durable remissions in treatment-naïve patients, the β-emitting radionuclides used in current RIT schemes may not be ideal for irradiating the microscopic tumors and the isolated tumor cells present in the setting of minimal residual disease (MRD). RIT with α-emitting radionuclides may be advantageous in the treatment of MRD because the short path length and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to the surrounding normal tissues. Our group has successfully demonstrated that pretargeted RIT (PRIT) using streptavidin (SA)-Ab and radiolabeled biotin allows rapid specific localization of radioactivity at tumor sites. PRIT using α-emitting radionuclides may be particularly attractive since the most promising α-emitting radionuclides in clinical settings, such as 213Bi (t½ = 46 min), have short half-lives and pretargeting allows the delivery of radioactivity to tumor sites before the activity decays. We therefore performed in vivo studies to evaluate the biodistribution of 213Bi with PRIT. Athymic mice with B-cell NHL (Ramos) xenografts received a tetravalent anti-CD20 (1F5) single-chain (scFv)4SA fusion protein (FP) or a CC49 (scFv)4SA FP (non-binding negative control) followed by an N-acetyl galactosamine clearing agent (CA) and subsequent 213Bi-DOTA-biotin infusion. Tumors, blood, and major organs were collected to determine the percent injected dose per gram (%ID/g) at various time points within ∼3 half-lives of 213Bi. Maximal tumor uptake for 1F5 (scFv)4SA FP was 16.5 ± 7.0 %ID/g at 90 minutes vs. 2.3 ± 0.9 %ID/g for the control FP (p = 0.0001). Biodistributions of 213Bi using a conventional RIT scheme with directly labeled Ab were also evaluated. Athymic mice with Ramos xenografts received 213Bi labeled 1F5 Ab or 213Bi labeled HB8181 Ab (a murine isotype matched nonbinding control). Maximum tumor uptake for 1F5 Ab was 3.0 ± 0.9 %ID/g at 180 minutes vs. 2.3 ± 0.7 %ID/g for the control Ab (p = 0.171). There were no significant differences in tumor uptake and normal organ distribution between the two Ab within 180 minutes of radiolabeled Ab injection presumably due to the protracted circulating half-life of radiolabeled Abs. These results were concordant with our previous experiments using other radionuclides, showing that maximal targeting of radiolabeled Ab occurs between 20 to 24 hours; well beyond the effective half-life of 213Bi. When the results of PRIT and RIT studies were directly compared, tumor-to-blood ratios were 58 to 426-fold higher with PRIT than with conventional RIT. Tumor-to-normal organ ratios of nearly 100:1 were observed with PRIT compared to 3:1 or less with conventional RIT. Using the most favorable PRIT schemes defined in the biodistribution experiments, the therapeutic efficacy of 213Bi was evaluated. Mice treated with PRIT using 1F5 (scFv)4SA FP followed by a CA and 600 μCi 213Bi-DOTA-biotin experienced significant delays in tumor growth. The 1F5 (scFv)4SA FP treated animals had a mean tumor volume of 0.01 ± 0.02 vs. 203.38 ± 83.03 mm3 for the CC49 control group at 19 days (p = 0.0006). The median survival for 1F5 group was not reached after 90 days; whereas, the median survival was 23 days for the CC49 group (p = 0.0019) and 16 days for untreated mice (p = 0.0023). The treatment was well tolerated, with no treatment-related mortalities in any group. These data demonstrate that PRIT using 213Bi has a favorable biodistribution profile and excellent therapeutic efficacy. This model may be particularly effective in MRD settings and further studies are ongoing. Disclosures: No relevant conflicts of interest to declare.

Targeting CD20 in Follicular NHL: Novel Anti-CD20 Therapies, Antibody Engineering, and the Use of Radioimmunoconjugates

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 335-339 ◽  
Author(s):  
John P. Leonard
Keyword(s):  
Biologic Agents ◽  
Antibody Engineering ◽  
Ibritumomab Tiuxetan ◽  
Aggressive Disease ◽  
Non Hodgkin Lymphoma ◽  
Resistant Disease ◽  
Complement Dependent Cytotoxicity ◽  
Anti Cd20 ◽  
Cd20 Antibodies ◽  
Enhance Activity

Abstract Rituximab (chimeric anti-CD20 monoclonal antibody) is widely employed in the treatment of patients with B cell non-Hodgkin lymphoma (NHL). This agent has activity in both indolent and aggressive disease, alone and in combination with chemotherapy. Unfortunately, however, many patients develop resistant disease. Ongoing efforts to improve outcomes include changes in dose and schedule, as well as the use of other biologic agents or antibodies that may enhance activity when administered together with rituximab. A relatively new focus is the development of engineered anti-CD20 antibodies that are optimized for their capability to mediate antibody-mediated cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Human or humanized structures have also been employed to potentially improve these attributes, as well as to improve on pharmacokinetics and immunogenicity. Other studies in NHL have clearly demonstrated that radiolabeled anti-CD20 antibodies (such as I-131 tositumomab and Y-90 ibritumomab tiuxetan) may be useful in relapsed and refractory disease, and have potential utility as part of initial treatment as well. Further studies of these modified anti-CD20 antibodies are ongoing in order to optimize their use for maximal clinical benefit.

Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma

Blood ◽  
2004 ◽  
Vol 104 (1) ◽  
pp. 227-236 ◽  
Author(s):  
Andres Forero ◽  
Paul L. Weiden ◽  
Julie M. Vose ◽  
Susan J. Knox ◽  
Albert F. LoBuglio ◽  
...  
Keyword(s):  
Fusion Protein ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Phase 1 ◽  
Whole Body ◽  
Single Chain ◽  
Phase 1 Trial ◽  
Non Hodgkin Lymphoma ◽  
Pretargeted Radioimmunotherapy ◽  
Anti Cd20

Abstract Pretargeted radioimmunotherapy (PRIT) has the potential to increase the dose of radionuclide delivered to tumors while limiting radiation to normal tissues. The purpose of this phase 1 trial is to assess safety of this multistep approach using a novel tetrameric single-chain anti-CD20–streptavidin fusion protein (B9E9FP) as the targeting moiety in patients with B-cell non-Hodgkin lymphoma (NHL), and to characterize its pharmacokinetics and immunogenicity. All patients received B9E9FP (160 mg/m2 or 320 mg/m2); either 48 or 72 hours later, a synthetic clearing agent (sCA) was administered (45 mg/m2) to remove circulating unbound B9E9FP. 90Yttrium (90Y; 15 mCi/m2)/111In (5 mCi)–DOTA-biotin was injected 24 hours later. There were 15 patients enrolled in the study. B9E9FP had a mean plasma half-life (T½) of 25 ± 6 hours with a reduction in plasma level of more than 95% within 6 hours of sCA administration. 90Y/111In-DOTA-biotin infusion resulted in rapid tumor localization and urinary excretion. The ratio of average tumor to whole-body radiation dose was 49:1. No significant hematologic toxicities were noted in 12 patients. There were 2 patients who had hematologic toxicity related to progressive disease. There were 2 complete remissions (90 and 325 days) and one partial response (297 days). B9E9FP performs well as the targeting component of PRIT with encouraging dosimetry, safety, and efficacy. A dose escalation trial of 90Y-DOTA-biotin in this format is warranted.

A Novel Bispecific CD38 Antibody Eradicates Multiple Myeloma in a Mouse Model Following Yttrium-90-DOTA Capture

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 118-118
Author(s):  
Damian J Green ◽  
Jon C Jones ◽  
Yukang Lin ◽  
Shani L. Frayo ◽  
Aimee L Kenoyer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Efficacy ◽  
Xenograft Model ◽  
Normal Organ ◽  
Athymic Nude Mice ◽  
Biodistribution Studies ◽  
Liver And Kidney ◽  
Anti Cd20 ◽  
Therapy Studies ◽  
Yttrium 90

Abstract BACKGROUND: Despite high rates of initial response to immunomodulatory agents and proteasome inhibitors, the vast majority patients living with multiple myeloma (MM) will ultimately die of progressive disease that is a function of persistent MM cell clones. The radiosensitivity of malignant plasma cells is well documented in clinical settings, and we have previously reported the therapeutic efficacy of a streptavidin-biotin (SAB) pretargeted radioimmunotherapy (PRIT) system delivering the β-emitter 90Y to CD38 antigen targets (Green, et al. Cancer Res. 2014). While SAB-PRIT is capable of disease eradication in mouse models, SA immunogenicity and interference by endogenous biotin may complicate clinical translation of these findings into human trials. METHODS: To prospectively address these potential limitations and to further enhance therapeutic efficacy of PRIT, we engineered an anti-human CD38 xanti-chelated radiometal fusion protein (FP) specifically designed to trap second-step radiolabeled ligand (Y-DOTA) using a very high affinity anti-Y-DOTA scFv (C825). The bispecific anti-CD38 FP construct (028Fc-C825) expressed in CHO cells was affinity purified, assessed by gel filtration chromatography and binding specificity to both CD38 and Y-DOTA was confirmed. In vivo experiments showed the absence of toxicity of the bispecific construct at a dose range of 0.14-2.8 nmol per mouse (n=5/group). Biodistribution studies were performed in athymic nude mice (n=5/group) bearing s.c. luciferase transduced NCI-H929Luc human MM xenograft tumors. Animals received 2.8 nmol (420 µg) of either 028-Fc-C825 (anti-CD38 FP) or an irrelevant matched negative control bi-specific FP 2H7-Fc-C825 (anti-CD20 FP) with the same modular IgG-scFv structure (NCI-H929Luc are CD20 negative). The bispecific FP was administered 23 hours prior to a synthetic DOTAY-Dextran clearing agent (CA; 5 µg) and 24 hours prior to administration of trace labeled 90Y-DOTA (2 µg). In therapy studies, athymic nude mice (n=10/group) bearing s.c. NCI-H929Luc human MM xenograft tumors received 2.8 nmol of either 028-Fc-C825 (anti-CD38 FP) or 2H7-Fc-C825 (anti-CD20 FP) 23 hours prior to synthetic DOTAY-Dextran CA and 24 hrs prior to 90Y-DOTA (2 µg; 1200 µCi per mouse). An activity range of 800 µCi to 1200 µCi was previously identified as optimal in a MM xenograft model using the high energy beta particle emitter 90Y (t1/2 = 64 hours) [Green, et al. Cancer Res. 2014]. RESULTS: Selective tumor targeting of 90Y ligand to CD38+ xenografts was observed following administration of the bispecific anti-CD38 FP. Blood, tumor and nonspecific organ uptakes of 028-Fc-C825 demonstrated tumor-to-normal organ absorbed ratios that were 15:1; 17:1; 9:1; and 13:1, respectively for blood, lung, liver and kidney; compared to 0.7:1; 1:1; 1:1 and 0.5:1, respectively, in mice pretargeted with 2H7-Fc-C825 (control). The bispecific anti-CD38 FP also resulted in tumor-to-normal organ ratios of absorbed radioactivity that were superior to those measured in animals receiving anti-CD38 SAB-PRIT (OKT10-SA chemical conjugate) in the same study (5:1; 8:1; 5:1 and 2:1 for blood, lung, liver and kidney respectively). In therapy studies, no animal in any group lost >7% of initial body weight and by day 11 anti-CD38 bispecific FP treated animals were 102.4% ± 3.4% of baseline weight. All mice in the control bispecific FP group experienced exponential MM tumor growth and 100% of these control animals required euthanasia within 27 days. All mice pretargeted with 028-Fc-C825 (anti-CD38 bispecific FP) demonstrated tumor response by day 6. After 45 days, 100% of the anti-CD38 bispecific FP treated animals remained alive (Figure A) and objective remissions were observed within 18 days in 100% of the mice treated with 028-Fc-C825 followed by 1200 µCi of 90Y-DOTA, including 90% complete remissions (no detectable tumor in 028Fc-C825 treated mice) compared to tumors that were 2040 ± 1389% of initial tumor volume [p<0.0001, Student's t-test] in untreated control animals by day 12 (Figure B). CONCLUSION: Biodistribution studies demonstrate MM tumor specific targeting after anti-CD38 xanti-chelated radiometal FP with minimal levels of yttrium-90 radioactivity detected in normal organs. Tumor responses are very encouraging in this MM xenograft model and results support clinical evaluation of bispecific anti-CD38 FP PRIT in MM. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Improved Responses and Cures with Less Hematologic Toxicity Using Anti-CD20 Bispecific Antibody Pretargeted Radionuclides Compared to Directly Radiolabeled IgG in a NHL Model.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2344-2344
Author(s):  
David M. Goldenberg ◽  
Robert M. Sharkey ◽  
Habibe Karacay ◽  
Chien-Hsing Chang ◽  
Edmund A. Rossi ◽  
...  
Keyword(s):  
Bispecific Antibody ◽  
Initial Response ◽  
Response Rates ◽  
Hematologic Toxicity ◽  
Tumor Uptake ◽  
Non Hodgkin Lymphoma ◽  
Counting Data ◽  
Anti Cd20 ◽  
Cure Rates ◽  
Human B Cell

Abstract Directly radiolabeled anti-CD20 IgGs approved for the treatment of follicular and transformed non-Hodgkin lymphoma produce higher response rates than rituximab. However, these treatments result in severe and protracted hematologic toxicity, which is directly related to the slow blood clearance of these radiolabeled products. Pretargeting procedures separate radionuclide-targeting from the slow antibody-targeting step, and because the radiolabeled compound is small in size, it clears rapidly and thoroughly from the blood and body in just a few hours, minimizing radiation exposure. We have developed a novel recombinant and humanized Tri-Fab bispecific antibody (bsMAb) for pretargeting using the modular Dock-and-Lock procedure. This bsMAb divalently binds to CD20, with the monovalent Fab binding to a unique peptide hapten (HSG) that carries the therapeutic radionuclide. Nude mice bearing established (0.5 to 0.9 cm3) subcutaneous Ramos human B-cell lymphomas were given a single dose of either a 90Y-humanized anti-CD20 IgG (150 and 175 μCi; 50 μg) or a bsMAb-pretargeted 90Y-DOTA-HSG-peptide (150, 250, 500, and 700 μCi). Tissue counting data derived 24 h after injecting the radiolabeled product showed similar tumor uptake between the IgG and pretargeted peptide, but tumor/blood ratios were &gt;1000:1 for the pretargeted peptide vs. 1:1 for the IgG. At both 90Y-IgG doses, blood counts decreased ∼90% for 2 weeks after treatment, while the pretargeted groups only decreased ∼60% at the 700 μCi dose to as low as a 25% decrease at the 250 μCi dose, with full recoveries occurring within 2 weeks of the nadir. The severe hematologic toxicity also resulted in 2/10 and 4/10 deaths within 2 weeks of the 150- and 175-μCi 90Y-IgG doses, respectively. In the remaining animals, after experiencing an initial response, all tumors progressed to ≥1.5 cm3 within 3 weeks of treatment. Only 1/10 animals given 500 μCi of the pretargeted dose showed tumor progression, with all others in this group and the 700-μCi-group showing no evidence of disease. Earlier studies have shown 40%, 59%, and 90% cure rates after 14 to 18 weeks evaluation with 150, 250, and 500 μCi, respectively, of the bsMAb-pretargeted 90Y-peptide (n = 10 to 22 animals). These studies demonstrate that bsMAb pretargeting significantly improves response rates, with durable cures and without the excessive hematologic toxicity commonly associated with directly radiolabeled antibodies. (Supported in part from USPHS grant P01-CA103985.)

Radioimmunotherapy of Non-Hodgkin Lymphoma is Improved without Increasing Toxicity by Combination with Antibody immunotherapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1588-1588
Author(s):  
Robert M Sharkey ◽  
M. Jules Mattes ◽  
Habibe Karacay ◽  
Chien-Hsing Chang ◽  
Edmund A Rossi ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Treatment Regimen ◽  
Bispecific Antibody ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Tumor Uptake ◽  
Non Hodgkin Lymphoma ◽  
Antibody Immunotherapy ◽  
Anti Cd20 ◽  
Therapeutic Responses

Abstract Radioimmunotherapy (RAIT) is an effective treatment for follicular and transformed non-Hodgkin lymphoma (NHL) that combines a small amount of a radiolabeled anti-CD20 IgG with a large pre-dose of unlabeled anti-CD20 IgG (~900 mg). While a portion of this pre-dose is used to reduce radioconjugate uptake in the spleen and increase its circulation half-life, an excessive amount of unlabeled anti-CD20 IgG could interfere with the radioconjugate’s uptake in the tumor, perhaps compromising RAIT’s full therapeutic potential. In an animal model bearing the Burkitt human B-cell lymphoma xenografts (Ramos), we explored alternative approaches to enhance radionuclide targeting to the tumor without compromising the therapeutic benefit derived from the unconjugated anti-CD20 IgG and without increasing host toxicity. One approach utilized a 90Y-labeled, humanized anti-CD22 IgG (epratuzumab) combined with a therapeutic pre-dose of 1.0 mg of the humanized anti-CD20 IgG (veltuzumab) 1 day before the 90Y-epratuzumab (0.05 mg/0.175 mCi), with 3 additional veltuzumab doses of 0.5 mg given weekly thereafter. Biodistribution studies showed the anti-CD20 IgG did not affect tumor uptake of the 90Y-epratuzumab, but when 1.0 mg of anti-CD20 veltuzumab (human equivalent of 280 mg) was given 1 day, or even 1 h, in advance of radiolabeled veltuzumab, that tumor uptake was reduced 50%. The combination of 90Y-epratuzumab with unlabeled veltuzumab resulted in 80% (12/15) of the animals being tumor-free 18 weeks later, whereas either treatment alone was only able to induce a transient response within 1 week that lasted no more than 2 weeks. The addition of a similar treatment regimen of unlabeled epratuzumab or unlabeled veltuzumab to 90Y-veltuzumab produced similar short-term responses as 90Y-veltuzumab alone, with all tumors regrowing within 1–2 weeks of achieving their peak response. However, when the veltuzumab treatment regimen was initiated 1 week after the 90Y-veltuzumab dose, 6/10 of the animals were tumor-free 18 weeks later. This combination therapy was also evaluated for the method of pretargeted RAIT. We also have found that anti-CD20 bispecific antibody pretargeting that localizes a 90Y-labeled hapten-peptide provides improved therapeutic responses compared to the directly radiolabeled 90Y-veltuzumab without the associated severe hematologic toxicity at only 30% of its maximum tolerated dose. Tumor uptake of the 90Y-hapten-peptide was reduced by as much as 70% when 1 mg of veltuzumab was given as a pre-dose that resulted in a significant impairment of anti-tumor responses. However, therapeutic responses were enhanced when the pre-dose was lowered to 0.25 mg, despite a 50% reduction in tumor uptake of the pretargeted 90Y-hapten-peptide. Additional enhancements occurred when unlabeled veltuzumab was given after the 90Y-hapten-peptide pretargeting. These studies suggest a number of strategies that can enhance the therapeutic response of targeted radionuclides, including the use of anti-CD22 radioconjugate combined with non-competing veltuzumab, reducing the anti-CD20 pre-dose that is given with an anti-CD20 based targeting procedure (with emphasis on using the anti-CD20 IgG as a consolidation therapy), and applying RAIT with bispecific antibody pretargeting that is able to enhance anti-tumor responses with less severe hematologic toxicity that also benefits from consolidated veltuzumab therapy. Thus, combination direct RAIT or pre-targeted RAIT with non-competing antibody immunotherapy should be tested clinically. (Supported in part by a PHS grant P01 CA103985 from the NCI.)

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