Novel Antibody Drug Conjugates Targeting Tumor-Associated Receptor Tyrosine Kinase ROR2 by Functional Screening of Fully Human Antibody Libraries Using Transpo-mAb Display on Progenitor B Cells

Hellmann, Ina; Waldmeier, Lorenz; Bannwarth-Escher, Marie-Christine; Maslova, Kseniya; Wolter, Fabian I.; Grawunder, Ulf; Beerli, Roger R.

doi:10.3389/fimmu.2018.02490

Cited by 21 publications

(11 citation statements)

References 66 publications

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“…However, as in the case of ROR1, a mAb binding to an intracellular epitope of ROR2 may be a preferred reagent for IHC and, as such, a suitable companion diagnostic. A recent study by Hellmann et al described the selection of fully human anti-human ROR2 mAbs and their conversion to antibody-drug conjugates (43). Although these mAbs are human, most are not cross-reactive with mouse ROR2.…”

Section: Discussionmentioning

confidence: 99%

Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications

Goydel

Weber

Peng

et al. 2020

Journal of Biological Chemistry

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Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.

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Section: Discussionmentioning

confidence: 99%

Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications

Goydel

Weber

Peng

et al. 2020

Journal of Biological Chemistry

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“…Moreover, XBR2-401 was used as a base for designing a biAb (ROR2 x CD3), showing specificity for ROR2 in vitro [ 199 ]. Further investigation concerning ROR2-targeting ADCs are also in progress [ 200 ]. One potential candidate might be BA3021, a CAB-ROR2-ADC, which reversibly interacts with ROR2 in conditions reflecting the tumor microenvironment, but less so in normal tissue [ 201 ].…”

Section: Targeted Therapymentioning

confidence: 99%

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

Menck

Heinrichs

Baden

et al. 2021

Cells

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The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.

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“…ROR2 has been proposed as a therapeutic target in cancer [ 5 ] and antibody-based therapeutic tools have been already developed [ 58 , 59 ]. Further, the effect of targeting ROR2 is being evaluated in phase 1 and 2 clinical trials (NCT03504488, NCT03393936, and NCT03960060) for patients with advanced cancer.…”

Section: Discussionmentioning

confidence: 99%

ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation

et al. 2021

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Background Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. Methods Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. Results Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. Conclusion We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.

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Novel Antibody Drug Conjugates Targeting Tumor-Associated Receptor Tyrosine Kinase ROR2 by Functional Screening of Fully Human Antibody Libraries Using Transpo-mAb Display on Progenitor B Cells

Cited by 21 publications

References 66 publications

Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications

Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation

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