New concepts in monoclonal antibody based radioimmunodiagnosis and radioimmunotherapy of carcinoma

Schlom, Jeffrey; Milenic, Diane E.; Roselli, Mario; Colcher, David; Bird, Robert E.; Johnson, Syd; Hardman, Karl D.; Guadagni, Fiorella; Greiner, John W.

doi:10.1016/0883-2897(91)90070-2

Cited by 11 publications

(5 citation statements)

References 13 publications

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“…Predosing with a carefully chosen dose of an unconjugated parental monoclonal antibody (mAb) is a potential means of decreasing ADC uptake by saturating receptors expressed in non-tumor tissues while preserving tumor uptake. The predosing strategy relies on blockage of binding sites with a less potent unconjugated antibody [12], and has been successfully applied in nuclear imaging and radioimmunotherapy [13–15]. Although predosing has been successful in increasing the tumor localization of radioimmunoconjugates in xenograft models and in the clinic [16–18], its effects on ADC efficacy are less understood.…”

Section: Introductionmentioning

confidence: 99%

Biodistribution and efficacy of an anti-TENB2 antibody-drug conjugate in a patient-derived model of prostate cancer

Boswell¹,

Yadav²,

Mundo³

et al. 2019

Oncotarget

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TENB2, a transmembrane proteoglycan protein, is a promising target for antibody drug conjugate (ADC) therapy due to overexpression in human prostate tumors and rapid internalization. We previously characterized how predosing with parental anti-TENB2 monoclonal antibody (mAb) at 1 mg/kg in a patient-derived LuCap77 explant model with high (3+) TENB2 expression could (i) block target-mediated intestinal uptake of tracer (& 0.1 mg/kg) levels of radiolabeled anti-TENB2-monomethyl auristatin E ADC while preserving tumor uptake, and (ii) maintain efficacy relative to ADC alone. Here, we systematically revisit this strategy to evaluate the effects of predosing on tumor uptake and efficacy in LuCap96.1, a low TENB2-expressing (1+) patient-derived model that is more responsive to ADC therapy than LuCap77. Importantly, rather than using tracer (& 0.1 mg/kg) levels, radiolabeled ADC tumor uptake was assessed at 1 mg/kg – one of the doses evaluated in the tumor growth inhibition study – in an effort to bridge tissue distribution (PK) with efficacy (PD). Predosing with mAb up to 1 mg/kg had no effect on efficacy. These findings warrant further investigations to determine whether predosing prior to ADC therapy might improve therapeutic index by preventing ADC disposition and possible toxicological liabilities in antigen-expressing healthy tissues.

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Section: Introductionmentioning

confidence: 99%

Biodistribution and efficacy of an anti-TENB2 antibody-drug conjugate in a patient-derived model of prostate cancer

Boswell¹,

Yadav²,

Mundo³

et al. 2019

Oncotarget

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“…This strategy has been successfully applied in nuclear imaging and radioimmunotherapy (6)(7)(8). Predosing often improves biodistribution into the effect compartment, yielding improved tumor accumulation of radioimmunoconjugates in xenograft models and in the clinic (9)(10)(11).…”

mentioning

confidence: 99%

Differential Effects of Predosing on Tumor and Tissue Uptake of an¹¹¹In-Labeled Anti-TENB2 Antibody–Drug Conjugate

Boswell¹,

Mundo²,

Zhang³

et al. 2012

J Nucl Med

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TENB2, also known as tomoregulin or transmembrane protein with epidermal growth factor-like and 2 follistatin-like domains, is a transmembrane proteoglycan overexpressed in human prostate tumors. This protein is a promising target for antimitotic monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADC) therapy. Nonlinear pharmacokinetics in normal mice suggested that antigen expression in normal tissues may contribute to targeted mediated disposition. We evaluated a predosing strategy with unconjugated antibody to block ADC uptake in target-expressing tissues in a mouse model while striving to preserve tumor uptake and efficacy. Methods: Unconjugated, unlabeled antibody was preadministered to mice bearing the TENB2-expressing human prostate explant model, LuCaP 77, followed by a single administration of 111 In-labeled anti-TENB2-MMAE for biodistribution and SPECT/CT studies. A tumor-growth-inhibition study was conducted to determine the pharmacodynamic consequences of predosing. Results: Preadministration of anti-TENB2 at 1 mg/kg significantly increased blood exposure of the radiolabeled ADC and reduced intestinal, hepatic, and splenic uptake while not affecting tumor accretion. Similar tumor-to-heart ratios were measured by SPECT/CT at 24 h with and without the predose. Consistent with this, the preadministration of 0.75 mg/kg did not interfere with efficacy in a tumor-growth study dosed at 0.75 mg or 2.5 mg of ADC per kilogram. Conclusion: Overall, the potential to mask peripheral, nontumor antigen uptake while preserving tumor uptake and efficacy could ameliorate toxicity and may significantly affect future dosing strategies for ADCs.

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“…46 Finally, preclinical therapeutic studies using MAb CC49 conjugated to 131 I, 90 Y, and 177 Lu have shown a 3‐ to 5‐fold improvement in therapeutic efficacy, producing cures in these preclinical models. 30,50…”

Section: Second Generation Monoclonal Antibodies To Tag‐72mentioning

confidence: 99%

“…46 Finally, preclinical therapeutic studies using MAb CC49 conjugated to 131 I, 90 Y, and 177 Lu have shown a 3-to 5-fold improvement in therapeutic efficacy, producing cures in these preclinical models. 30,50 Using DNA recombinant techniques, we have produced a range of smaller fragments called single-chain Fv (scFv) for murine MAb CC49. The valency is one of the hallmarks by which significant improvement in functional affinity and avidity of scFv can be achieved.…”

Section: Second Generation Monoclonal Antibodies To Tag-72mentioning

confidence: 99%

Single‐Chain Antibodies in Pancreatic Cancer

Colcher

Pavlínková

Beresford

et al. 1999

Annals of the New York Academy of Sciences

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Pancreatic cancer is a therapeutic challenge for surgical and medical oncology. Development of specific molecular tracers for the diagnosis and treatment of this lethal cancer has been one of our major goals. Monoclonal antibodies (MAbs) have been successfully used as selective carriers for delivering radionuclides, toxins or cytotoxic drugs to malignant cell populations; therefore, monoclonal antibody technology has led to a significant amount of research into optimizing targeted therapy. This targeted therapy results in the selective concentration of cytotoxic agents or radionuclides in tumors and should lessen the toxicity to normal tissues, which would normally limit the dosage and effectiveness of systemically administered drugs. The MAb CC49 reacts with a unique disaccharide, Sialyl-Tn, present on tumor-associated mucin (TAG-72) expressed by a majority of human adenocarcinomas. The unique Sialyl-Tn epitope has provided a potential target for immunotherapy of cancer. A single chain Fv (scFv) recombinant protein from CC49 MAb was prepared by engineering the DNA fragments for coding heavy-chain and light-chain variable regions with an appropriate oligonucleotide linker. scFv molecules, when compared to intact MAbs and the more conventional enzymatically derived F(ab')2 and Fab' fragments, offer several advantages as carriers for the selective delivery of radionuclides to tumors. The divalent antibody fragments (sc(Fv)2 or (scFv)2) display an affinity constant similar to that of the intact CC49 IgG and are stable with storage, and after radiolabeling. In preclinical studies, both the covalent and the non-covalent dimeric scFvs exhibit excellent tumor targeting properties with characteristics similar to those of the monomer, e.g., the rapid blood clearance, low kidney uptake and small size suitable for rapid penetration through tumor tissue. Increased tumor targeting of the dimers are probably due to their increased functional affinity attributable to valency, coupled with their higher molecular weight and fewer interactions with normal organs. These properties make these constructs superior to monovalent CC49 scFv. The relatively high tumor uptake, the in vitro and in vivo targeting specificity, and the stability in storage demonstrated by the dimeric CC49 sc(Fv)2 makes it a promising delivery vehicle for therapeutic applications in pancreatic cancer.

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New concepts in monoclonal antibody based radioimmunodiagnosis and radioimmunotherapy of carcinoma

Cited by 11 publications

References 13 publications

Biodistribution and efficacy of an anti-TENB2 antibody-drug conjugate in a patient-derived model of prostate cancer

Biodistribution and efficacy of an anti-TENB2 antibody-drug conjugate in a patient-derived model of prostate cancer

Differential Effects of Predosing on Tumor and Tissue Uptake of an¹¹¹In-Labeled Anti-TENB2 Antibody–Drug Conjugate

Single‐Chain Antibodies in Pancreatic Cancer

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New concepts in monoclonal antibody based radioimmunodiagnosis and radioimmunotherapy of carcinoma

Cited by 11 publications

References 13 publications

Biodistribution and efficacy of an anti-TENB2 antibody-drug conjugate in a patient-derived model of prostate cancer

Biodistribution and efficacy of an anti-TENB2 antibody-drug conjugate in a patient-derived model of prostate cancer

Differential Effects of Predosing on Tumor and Tissue Uptake of an111In-Labeled Anti-TENB2 Antibody–Drug Conjugate

Single‐Chain Antibodies in Pancreatic Cancer

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Product

Resources

About

Differential Effects of Predosing on Tumor and Tissue Uptake of an¹¹¹In-Labeled Anti-TENB2 Antibody–Drug Conjugate