Antibody Engineering: Optimizing the Delivery Vehicle

Milenic, Diane E.

doi:10.1002/9780470613214.ch1

Cited by 4 publications

(5 citation statements)

References 147 publications

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“…23 Affibodies are medium-sized peptides (6.5 kDa) derived from a nonimmunoglobulin a-helix-based scaffold with similar or higher affinity than some mAb. 59,42 ABY-025 is a secondgeneration affibody molecule with reduced nonspecific liver uptake that binds to domain III of the extracellular portion of HER2. Since trastuzumab and pertuzumab bind to domains IV and II, respectively, ABY-025 would promote a noncompetitive interaction, which may provide an important advantage for using this imaging agent in the presence of therapeutic concentrations of trastuzumab and/or pertuzumab.…”

Section: Antibodies Fragments and Other Small Moleculesmentioning

confidence: 99%

Targeting HER2 in Nuclear Medicine for Imaging and Therapy

2018

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Since its discovery, the human epidermal growth factor 2 (HER2) has been extensively studied. Presently, there are 2 standard diagnostic techniques to assess HER2 status in biopsies: immunohistochemistry and fluorescence in situ hybridization. While these techniques have played an important role in the treatment of patients with HER2-positive cancer, they both require invasive biopsies for analysis. Moreover, the expression of HER2 is heterogeneous in breast cancer and can change over the course of the disease. Thus, the degree of HER2 expression in the small sample size of biopsied tumors at the time of analysis may not represent the overall status of HER2 expression in the whole tumor and in between tumor foci in the metastatic setting as the disease progresses. Unlike biopsy, molecular imaging using probes against HER2 allows for a noninvasive, whole-body assessment of HER2 status in real time. This technique could potentially select patients who may benefit from HER2-directed therapy and offer alternative treatments to those who may not benefit. Several antibodies and small molecules against HER2 have been labeled with different radioisotopes for nuclear imaging and/or therapy. This review presents the most recent advances in HER2 targeting in nuclear medicine focusing on preclinical and clinical studies.

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Section: Antibodies Fragments and Other Small Moleculesmentioning

confidence: 99%

Targeting HER2 in Nuclear Medicine for Imaging and Therapy

2018

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“…3 Reduction in the size of the mAb, achieved through enzymatic digestion or genetic engineering, is another path taken by investigators in dealing with the obstacles inherent in the use of an intact immunoglobulin as a radiopharmaceutical vector. 38 Fragments, such as an F(ab¢) 2 , can be readily obtained using pepsin without loss of immunoreactivity. 13,15,39 F(ab¢) 2 fragments have been shown to have a faster extravasation rate and localization to tumor, greater penetration of the tumor, and have an overall lower residence time of unbound RIC in the body.…”

Section: Figmentioning

confidence: 99%

Exploration of a F(ab′)₂Fragment as the Targeting Agent of α-Radiation Therapy: A Comparison of the Therapeutic Benefit of Intraperitoneal and Intravenous Administered Radioimmunotherapy

Milenic

Kim

Baidoo

et al. 2018

Cancer Biotherapy and Radiopharmaceuticals

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Refinement of treatment regimens enlisting targeted α-radiation therapy (TAT) is an ongoing effort. Among the variables to consider are the target molecule, radionuclide, dosage, and administration route. The panitumumab F(ab') fragment targeting epidermal growth factor receptor tolerated modification with the TCMC chelate as well as radiolabeling with Pb orPb. Good specific activity was attained when the immunoconjugate was labeled with Pb (9.6 ± 1.4 mCi/mg). Targeting of LS-174T tumor xenografts with thePb-panitumumab F(ab') demonstrated comparable amounts of uptake to the similarly radiolabeled panitumumab IgG. A dose escalation study was performed to determine an effective working dose for both intraperitoneal (i.p.) and intravenous (i.v.) injections of Pb-panitumumab F(ab'). Therapeutic efficacy, with modest toxicity, was observed with 30 μCi given i.p. Results for the i.v. administration were not as definitive and the experiment was repeated with a higher dose range. From this study, 20 μCi given i.v. was selected as the effective working dose. A subsequent therapy study combined gemcitabine or paclitaxel with i.v. Pb-panitumumab F(ab'), which increased the median survival (MS) of LS-174T tumor-bearing mice to 208 and 239 d, respectively. Meanwhile, the MS of mice treated with i.v. Pb-panitumumab F(ab') alone was 61 and 11 d for the untreated group of mice. In conclusion, the panitumumab F(ab') fragment whether given by i.p. or i.v. injection, is a viable candidate as a delivery vector for TAT of disseminated i.p. disease.

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“…Monoclonal antibodies (mAb) and their derivatives are one example that have long been used clinically to deliver radionuclides for radioimmunotherapy and scintigraphy (9,116) because mAbs enable radionuclides to be targeted to cells that express the corresponding antigen. However, the clinical application of MAbs has been hampered by several issues: 1) undesired immunogenicity generated by xenogeneic mAbs (91); 2) inadequate accumulation or penetration of mAbs inside diseased tissues because of their large size or their high affinity to antigens proximal to the vascular space; and 3) undesired accumulation of the mAbs in healthy organs, such as the kidney (100). These issues are gradually being resolved with new advances in genetic engineering, such as antibody humanization and the generation of smaller, but highly potent antibody fragments (47,99,134,135,143).…”

Section: Engineered Self-assembly On the Nanoscalementioning

confidence: 99%

“…As of 2008, these two approaches have led to a total of 61 mAbs in clinical development (91). Two of these mAbs, adalimumab, and panitumumab, have been approved by the FDA for the treatment of inflammatory diseases and colorectal cancer, respectively (43,100,124). Although largely developed as therapeutics, these human mAbs are also useful for the delivery of small molecule therapeutic and imaging agents.…”

Section: Engineered Self-assembly On the Nanoscalementioning

confidence: 99%

Nanoscale Self-Assembly for Delivery of Therapeutics and Imaging Agents

Chen¹,

McDaniel²,

MacKay³

et al. 2011

technol innov

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Self-assemblies are complex structures spontaneously organized from simpler subcomponents, primarily through noncovalent interactions. These structures are being exploited as delivery vehicles of therapeutic and imaging agents. They have two unique advantages in comparison to other vehicles: 1) they are able to assume complex structures that are difficult to attain by chemical synthesis, and 2) the dissociation of self-assembled structures can be triggered by external stimuli, which can serve as a mechanism of payload release. In this review, we discuss two naturally occurring (proteins and viral capsids) and five engineered self-assemblies (vesicles, micelles, proteins, hydrogels, and inclusion complexes) that are under development for delivery of drugs and imaging agents. For each class of self-assembled supramolecular structures, we examine its structural and physicochemical properties, and potential applications within the context of assembly, loading, and payload release.

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Antibody Engineering: Optimizing the Delivery Vehicle

Cited by 4 publications

References 147 publications

Targeting HER2 in Nuclear Medicine for Imaging and Therapy

Targeting HER2 in Nuclear Medicine for Imaging and Therapy

Exploration of a F(ab′)₂Fragment as the Targeting Agent of α-Radiation Therapy: A Comparison of the Therapeutic Benefit of Intraperitoneal and Intravenous Administered Radioimmunotherapy

Nanoscale Self-Assembly for Delivery of Therapeutics and Imaging Agents

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Antibody Engineering: Optimizing the Delivery Vehicle

Cited by 4 publications

References 147 publications

Targeting HER2 in Nuclear Medicine for Imaging and Therapy

Targeting HER2 in Nuclear Medicine for Imaging and Therapy

Exploration of a F(ab′)2Fragment as the Targeting Agent of α-Radiation Therapy: A Comparison of the Therapeutic Benefit of Intraperitoneal and Intravenous Administered Radioimmunotherapy

Nanoscale Self-Assembly for Delivery of Therapeutics and Imaging Agents

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Product

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Exploration of a F(ab′)₂Fragment as the Targeting Agent of α-Radiation Therapy: A Comparison of the Therapeutic Benefit of Intraperitoneal and Intravenous Administered Radioimmunotherapy