The Human Combinatorial Antibody Library HuCAL GOLD Combines Diversification of All Six CDRs According to the Natural Immune System with a Novel Display Method for Efficient Selection of High-Affinity Antibodies

Rothe, Christine; Urlinger, Stefanie; Löhning, Corinna; Prassler, Josef; Stark, Yvonne; Jäger, Ute; Hubner, Bernd; Bardroff, Michael; Pradel, Ingrid; Boss, Melanie; Bittlingmaier, Renate; Bataa, Tschimegma; Frisch, Christian; Brocks, Bodo; Honegger, Annemarie; Urban, Margit

doi:10.1016/j.jmb.2007.12.018

Cited by 227 publications

(202 citation statements)

References 74 publications

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“…OMP-18R5 was generated by panning the HuCAL GOLD phage-display library (MorphoSys) with recombinant FZD7 protein (42). DNA fragments encoding the fAb generated from the phage display library were subcloned into a full-length human IgG2 expression vector.…”

Section: Methodsmentioning

confidence: 99%

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

Gurney

Axelrod

Bond

et al. 2012

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

514

435

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The Wnt/β-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting the Wnt pathway with a monoclonal antibody, OMP-18R5. This antibody, initially identified by binding to Frizzled 7, interacts with five Fzd receptors through a conserved epitope within the extracellular domain and blocks canonical Wnt signaling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, this antibody inhibits the growth of a range of tumor types, reduces tumor-initiating cell frequency, and exhibits synergistic activity with standard-of-care chemotherapeutic agents.differentiation | cancer stem cell | pancreatic | breast | lung

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Section: Methodsmentioning

confidence: 99%

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

Gurney

Axelrod

Bond

et al. 2012

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

514

435

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“…Taking into account the high-bone mass phenotype of osteoblast/osteocyte-specific Lrp4 mutant mice and the absence of other gross abnormalities in high-bone mass patients with loss of LRP4 sclerostin facilitator function mutations, antagonizing this LRP4 function may provide a novel therapeutic opportunity for promoting bone gain. To test this hypothesis, we generated two human anti-LRP4 antibodies, which are fully cross-reactive with rat Lrp4, by in vitro affinity maturation (antibodies A and B) as described previously (35). Anti-LRP4 antibodies A and B (data only shown for A) were selected for binding to LRP4 in a highly specific as well as dose-dependent manner in vitro.…”

Section: Generation Of Anti-lrp4 Antibodies Blocking Sclerostin-facilmentioning

confidence: 99%

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

Chang

Krämer

Huber

et al. 2014

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

114

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We identified previously in vitro LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of the WNT (Winglesstype) antagonist sclerostin and found mutations disrupting this function to be associated with high bone mass in humans similar to patients lacking sclerostin. To further delineate the role of LRP4 in bone in vivo, we generated mice lacking Lrp4 in osteoblasts/osteocytes or osteocytes only. Lrp4 deficiency promoted progressive cancellous and cortical bone gain in both mutants, although more pronouncedly in mice deficient in osteoblast/osteocyte Lrp4, consistent with our observation in human bone that LRP4 is most strongly expressed by osteoblasts and early osteocytes. Bone gain was related primarily to increased bone formation. Interestingly, Lrp4 deficiency in bone dramatically elevated serum sclerostin levels whereas bone expression of Sost encoding for sclerostin was unaltered, indicating that osteoblastic Lrp4 retains sclerostin within bone. Moreover, we generated anti-LRP4 antibodies selectively blocking sclerostin facilitator function while leaving unperturbed LRP4-agrin interaction, which is essential for neuromuscular junction function. These antibodies increased bone formation and thus cancellous and cortical bone mass in skeletally mature rodents. Together, we demonstrate a pivotal role of LRP4 in bone homeostasis by retaining and facilitating sclerostin action locally and provide a novel avenue to bone anabolic therapy by antagonizing LRP4 sclerostin facilitator function.LRP4 | SOST | sclerostin | WNT | bone anabolism

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“…The HuCAL Gold Fab-phage library was obtained from MorphoSys AG and was prepared as described elsewhere (19), comprising a highly diverse library of 10 10 different monovalent phage encoded within phagemid vector pMORPH23 and allowing for monovalent CysDisplay of Fab fragments. Solid phase panning was carried out as described in the Supplementary Data.…”

Section: Antibody Discovery Using the Hucal Gold Fab-phage Librarymentioning

confidence: 99%

Therapeutic Mechanism and Efficacy of the Antibody–Drug Conjugate BAY 79-4620 Targeting Human Carbonic Anhydrase 9

Petrul

Schatz

Kopitz

et al. 2012

Molecular Cancer Therapeutics

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Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies (mAb) with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ectodomain of CAIX against the MorphoSys HUCAL Gold library of human Fabs. Highest affinity Fabs were converted to full-length IgGs and subjected to further characterization based upon their avidity and selectivity for CAIX, their capacity to undergo internalization in CAIX-expressing cell lines, and their selective localization to CAIX-positive human xenografted tumors when administered to mice as fluorescent conjugates. Through this selection process, the 3ee9 mAb was identified, which upon conjugation to monomethyl auristatin E through a self-immolative enzyme-cleavable linker yielded the potent and selective CAIX antibody-drug conjugate CAIX-ADC (BAY 79-4620). In preclinical human xenograft models in mice representing several tumor indications, BAY 79-4620 showed potent antitumor efficacy and in some models showed partial and complete tumor shrinkage even following a single dose. The mechanism of action was shown by histology to involve the sequelae of events typical of antitubulin agents. Efficacy in murine preclinical models correlated semiquantitatively, with CAIX expression levels as determined by immunohistochemistry and ELISA. These preclinical data collectively support the development of BAY 79-4620 for the treatment of cancer patients with CAIX overexpressing tumors. Mol Cancer Ther; 11(2); 340-9. Ó2011 AACR.

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The Human Combinatorial Antibody Library HuCAL GOLD Combines Diversification of All Six CDRs According to the Natural Immune System with a Novel Display Method for Efficient Selection of High-Affinity Antibodies

Cited by 227 publications

References 74 publications

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

Therapeutic Mechanism and Efficacy of the Antibody–Drug Conjugate BAY 79-4620 Targeting Human Carbonic Anhydrase 9

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