Chemically programmed antibodies: Endothelin receptor targeting CovX-Bodies™

Doppalapudi, Venkata Ramana; Tryder, Nancy; Li, Lingna; Aja, Teresa; Griffith, David A.; Liao, Francesca Fang; Roxas, Giovanni; Ramprasad, Mysore P.; Bradshaw, Curt W.; Barbas, Carlos F.

doi:10.1016/j.bmcl.2006.10.009

Cited by 53 publications

(42 citation statements)

References 12 publications

(16 reference statements)

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“…The AZD linker used here creates an irreversible covalent bond between a peptide and the scaffold and is different from that used in previously published CovX-Bodies based on a reversible diketone linker. The improvement on pharmacokinetics with these reversible linkers was not sufficient for most clinical drug development (20,21). A series of CovX-Bodies were made, as shown in Table 1, by moving the tether attachment site across the length of the peptide.…”

Section: Resultsmentioning

confidence: 99%

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Huang

Lai²,

Do³

et al. 2011

Clinical Cancer Research

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131

123

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Purpose: Angiopoietin-1 (Ang1) plays a key role in maintaining stable vasculature, whereas in a tumor Ang2 antagonizes Ang1's function and promotes the initiation of the angiogenic switch. Specifically targeting Ang2 is a promising anticancer strategy. Here we describe the development and characterization of a new class of biotherapeutics referred to as CovX-Bodies, which are created by chemical fusion of a peptide and a carrier antibody scaffold.Experimental Design: Various linker tethering sites on peptides were examined for their effect on CovXBody in vitro potency and pharmacokinetics. Ang2 CovX-Bodies with low nmol/L IC 50 s and significantly improved pharmacokinetics were tested in tumor xenograft studies alone or in combination with standard of care agents. Tumor samples were analyzed for target engagement, via Ang2 protein level, CD31-positive tumor vasculature, and Tie2 expressing monocyte penetration.Results: Bivalent Ang2 CovX-Bodies selectively block the Ang2-Tie2 interaction (IC 50 < 1 nmol/L) with dramatically improved pharmacokinetics (T ½ > 100 hours). Using a staged Colo-205 xenograft model, significant tumor growth inhibition (TGI) was observed (40%-63%, P < 0.01). Ang2 protein levels were reduced by approximately 50% inside tumors (P < 0.01), whereas tumor microvessel density (P < 0.01) and intratumor proangiogenic Tie2 CD11bþ cells (P < 0.05) were significantly reduced. When combined with sunitinib, sorafenib, bevacizumab, irinotecan, or docetaxel, Ang2 CovX-Bodies produced even greater efficacy ($80% TGI, P < 0.01). Conclusion: CovX-Bodies provide an elegant solution to overcome the pharmacokinetic-pharmacodynamic problems of peptides. Long-acting Ang2 specific CovX-Bodies will be useful as single agents and in combination with standard-of-care agents.

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Section: Resultsmentioning

confidence: 99%

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Huang

Lai²,

Do³

et al. 2011

Clinical Cancer Research

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131

123

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“…Notably, one common feature of Abs is that they are highly specific to a single target and, because of their clonal nature, a different Ab is required for each target. We have devised a new approach in which we modify the binding sites of a single Ab, 38C2, allowing it to be retargeted to more than one receptor [3][4][5][6][7] . Such Ab constructs are useful for adapter immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Preparation of integrin α(v)β(3)-targeting Ab 38C2 constructs

Sinha

Das

et al. 2007

Nat Protoc

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“…Here, we report a technology based on the aldolase catalytic antibodies (11)(12)(13)(14)(15) that facilitates rapid generation and optimization of unique bispecific agents termed bispecific CovX-Bodies. A bispecific CovX-Body contains two different pharmacophores, covalently bound to the nucleophilic heavy chain lysine at position 93 (according to Kabat numbering, ref.…”

mentioning

confidence: 99%

Chemical generation of bispecific antibodies

Doppalapudi

Huang

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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113

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Bispecific antibodies (BsAbs) are regarded as promising therapeutic agents due to their ability to simultaneously bind two different antigens. Several bispecific modalities have been developed, but their utility is limited due to problems with stability and manufacturing complexity. Here we report a versatile technology, based on a scaffold antibody and pharmacophore peptide heterodimers, that enables rapid generation and chemical optimization of bispecific antibodies, which are termed bispecific CovX-Bodies. Two different peptides are joined together using a branched azetidinone linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. As a prototype, we developed a bispecific antibody that binds both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) simultaneously, inhibits their function, shows efficacy in tumor xenograft studies, and greatly augments the antitumor effects of standard chemotherapy. This unique antiangiogenic bispecific antibody is in phase-1 clinical trials.

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Chemically programmed antibodies: Endothelin receptor targeting CovX-Bodies™

Cited by 53 publications

References 12 publications

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Preparation of integrin α(v)β(3)-targeting Ab 38C2 constructs

Chemical generation of bispecific antibodies

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