Antibody constructs in cancer therapy

Beckman, Robert A.; Weiner, Louis M.; Davis, Hugh M.

doi:10.1002/cncr.22402

Cited by 249 publications

(88 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A smaller size might facilitate extravasation and tumor penetration, thus increasing anti-tumor activity. [39][40][41] In support of this reasoning and in accordance with high specific bioactivity in in vitro assays, a first animal study using a xenograft Colo205 tumor model showed a potent and long-lasting tumor response without dose-limiting toxicity, though a direct comparison with pharmacodynamics data from Db-scTRAIL-95L8 20 is actually hampered due to differences in protein administration (doses, intraperitoneal vs. intravenous injection). To explore the therapeutic potential of fusion proteins comprising engineered scTRAIL variants in a broader way, the modification of pharmacokinetic properties by fusing half-life elongation moieties like Fc might be revealing.…”

Section: Discussionmentioning

confidence: 78%

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Siegemund

Seifert

Zarani³

et al. 2016

mAbs

View full text Add to dashboard Cite

Fusion proteins combining oligomeric assemblies of a genetically obtained single-chain (sc) variant of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with antibodies directed against tumorassociated antigens represent a promising strategy to overcome the limited therapeutic activity of conventional soluble TRAIL. To further improve the scTRAIL module in order to obtain a robust, thermostable molecule of high activity, we performed a comprehensive analysis of the minimal TNF homology domain (THD) and optimized linkers between the 3 TRAIL subunits constituting a scTRAIL. Through a stepwise mutagenesis of the N-and C-terminal region and the joining linker sequences, we generated bioactive scTRAIL molecules comprising a covalent linkage of the C-terminal Val280 and the Nterminal position 122 by only 2 amino acid residues in combination with conservative exchanges at positions 122 and 279. The increased thermal stability and solubility of such optimized scTRAIL molecules translated into increased bioactivity in the diabody-scTRAIL (Db-scTRAIL) format, exemplified here for an epidermal growth factor receptor-specific Db-scTRAIL. Additional modifications within the diabody linkers resulted in a fusion protein exerting high, target-dependent apoptosis induction in tumor cell lines in vitro and potent antitumor activity in vivo. Our results illustrate that protein engineering of scTRAIL and associated peptide linkers provides a promising strategy to develop antibody-scTRAIL fusion proteins as effective antitumor therapeutics.

show abstract

Section: Discussionmentioning

confidence: 78%

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Siegemund

Seifert

Zarani³

et al. 2016

mAbs

View full text Add to dashboard Cite

show abstract

“…A major determinant of speed of diffusion through tumors is molecular size. The rate of diffusion is approximately inversely proportional to the cube root of molecular weight [24,28]. Consequently, large macromolecules such as mAbs diffuse poorly explaining why larger tumor masses may be more difficult to treat by mAb therapy [24].…”

Section: Small Molecule Inhibitors and Monoclonal Antibodies In Breasmentioning

confidence: 99%

“…The expressed fusion protein is highly selective, site-specific, and versatile due to its high affinity for an array of BG substrates, e.g. toxins, fluorophores or photosensitizers [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66]. The conjugation of photosensitizers to SNAP-tag has made it an indispensable tool in photoimmunotherapy.…”

Section: Antibody-drug Conjugates and Fusion Proteins In Breast And Omentioning

confidence: 99%

Human Antibody Fusion Proteins/Antibody Drug Conjugates in Breast and Ovarian Cancer

Padayachee

Biteghe

Malindi

et al. 2017

Transfus Med Hemother

View full text Add to dashboard Cite

Considerable research efforts have been dedicated to understanding ovarian and breast cancer mechanisms, but there has been little progress translating the research into effective clinical applications. Hence, personalized/precision medicine has emerged because of its potential to improve the accuracy of tumor targeting and minimize toxicity to normal tissue. Targeted therapy in both breast and ovarian cancer has focused on antibodies, antibody drug conjugates (ADCs), and very recently the introduction of human antibody fusion proteins. Small molecule inhibitors and monoclonal antibodies (mAbs) are used in conjunction with chemotherapeutic drugs as a form of treatment but problems arise from a board expression of the target antigen in healthy tissues. Also, insufficient tumor penetration due to tight binding affinity and macromolecular size of mAbs compromise the efficacy of these ADCs. A more targeted approach is thus needed, and ADCs were designed to meet this need. However, in ADCs the method of conjugation of drug to antibody is >1, altering the structure of the drug which leads to off-target effects. Random conjugation also causes the drug to affect the pharmokinetics and biodistribution of the antibody and may cause nonspecific binding and internalization. Recombinant therapeutic proteins achieve controlled conjugation reactions and combine cytotoxicity and targeting in one molecule. They can also be engineered to extend half-life, stability and mechanism of action, and offer novel delivery routes. SNAP-tag fusion proteins are an example of a theranostic recombinant protein as they provide a unique antibody format to conjugate a variety of benzyl guanine modified labels, e.g. fluorophores and photosensitizers in a 1:1 stoichiometry. On the one hand, SNAP tag fusions can be used to optically image tumors when conjugated to a fluorophore, and on the other hand the recombinant proteins can induce necrosis/apoptosis in the tumor when conjugated to a photosensitizer upon exposure to a changeable wavelength of light. The dual nature of SNAP-tag fusions as both a diagnostic and therapeutic tool reinforces its significant role in cancer treatment in an era of precision medicine.

show abstract

“…Substantial effort has been directed toward localizing suitable EPT enzymes to tumor cells, βG or otherwise, but many approaches suffer distribution limitations or are currently unsafe for clinical use (Xu and McLeod, 2001;Beckman et al, 2007). In an effort to combat these limitations, we target βG to surface-exposed phosphatidylserine.…”

Section: Introductionmentioning

confidence: 99%

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

Guillen

Ruben

Virani

et al. 2016

Protein Engineering, Design and Selection

View full text Add to dashboard Cite

Enzyme prodrug therapy has the potential to remedy the lack of selectivity associated with the systemic administration of chemotherapy. However, most current systems are immunogenic and constrained to a monotherapeutic approach. We developed a new class of fusion proteins centered about the human enzyme β-glucuronidase (βG), capable of converting several innocuous prodrugs into chemotherapeutics. We targeted βG to phosphatidylserine on tumor cells, tumor vasculature and metastases via annexin A1/A5. Phosphatidylserine shows promise as a universal marker for solid tumors and allows for tumor type-independent targeting. To create fusion proteins, human annexin A1/A5 was genetically fused to the activity-enhancing 16a3 mutant of human βG, expressed in chemically defined, fed-batch suspension culture, and chromatographically purified. All fusion constructs achieved >95% purity with yields up to 740 μg/l. Fusion proteins displayed cancer selective cell-surface binding with cell line-dependent binding stability. One fusion protein in combination with the prodrug SN-38 glucuronide was as effective as the drug SN-38 on Panc-1 pancreatic cancer cells and HAAE-1 endothelial cells, and demonstrated efficacy against MCF-7 breast cancer cells. βG fusion proteins effectively enable localized combination therapy that can be tailored to each patient via prodrug selection, with promising clinical potential based on their near fully human design.

show abstract

Antibody constructs in cancer therapy

Cited by 249 publications

References 57 publications

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Human Antibody Fusion Proteins/Antibody Drug Conjugates in Breast and Ovarian Cancer

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

Contact Info

Product

Resources

About