Anti-LYPD1/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Ovarian Cancer

Lo, Amy A.; Johnston, Jennifer; Li, Ji; Mandikian, Danielle; Hristopoulos, Maria; Clark, Robyn; Nickles, Dorothee; Liang, Wei-Ching; Hötzel, Kathy; Dunlap, Debra; Pham, Thinh; Cai, Hao; Ovacik, Meric; Bravo-Perez, Daniel; Mai, Elaine; Slaga, Dionysos; Ellerman, Diego; Ziai, James; Tótpál, Klára; Lee, Genee; Boswell, C. Andrew; Payandeh, Jian; Wu, Yan; Junttila, Teemu T.

doi:10.1158/1535-7163.mct-20-0490

Cited by 8 publications

(9 citation statements)

References 36 publications

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“…Preclinical studies in mouse tumor models revealed a transient liver toxicity phenotype within 24 h following TDB treatment, which was resolved 4 days later. This phenotype included multiple necro‐inflammatory foci, variable perivascular, and periportal chronic inflammatory infiltrate, as well as focal early necrosis of hepatocytes surrounding the central vein, portal tracks, and within lobules (Lo et al , 2021 ). Furthermore, a single‐dose safety study in cynomolgus monkeys using TDB treatment revealed acute and transient off‐tumor activity, which is consistent with acute hepatocellular toxicity (Staflin et al , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

T cell‐dependent bispecific antibodies alter organ‐specific endothelial cell–T cell interaction

Himmels

Nguyen²,

Mitzner

et al. 2023

EMBO Reports

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Preclinical and clinical studies demonstrate that T cell-dependent bispecific antibodies (TDBs) induce systemic changes in addition to tumor killing, leading to adverse events. Here, we report an indepth characterization of acute responses to TDBs in tumorbearing mice. Contrary to modest changes in tumors, rapid and substantial lymphocyte accumulation and endothelial cell (EC) activation occur around large blood vessels in normal organs including the liver. We hypothesize that organ-specific ECs may account for the differential responses in normal tissues and tumors, and we identify a list of genes selectively upregulated by TDB in large liver vessels. Using one of the genes as an example, we demonstrate that CD9 facilitates ICAM-1 to support T cell-EC interaction in response to soluble factors released from a TDB-mediated cytotoxic reaction. Our results suggest that multiple factors may cooperatively promote T cell infiltration into normal organs as a secondary response to TDB-mediated tumor killing. These data shed light on how different vascular beds respond to cancer immunotherapy and may help improve their safety and efficacy.

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Section: Introductionmentioning

confidence: 99%

T cell‐dependent bispecific antibodies alter organ‐specific endothelial cell–T cell interaction

Himmels

Nguyen²,

Mitzner

et al. 2023

EMBO Reports

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“…1B, C). Due to the relatively low recovery (7.9%) of malignant epithelial cells from the ascites of the 11 HGSOC patients, Izar et al analyzed an additional 1297 viable malignant cells isolated on the basis of EPCAM+/CD24+ flow sorting and sequenced by full-length scRNA-seq SMART-seq2 17 . In these data, PAX8, LYPD1, MUC16 and MSLN were expressed in most malignant epithelial cells (92, 87, 97, and 95%, respectively) and still expressed in a small population of fibroblasts also captured (23,3,84, and 83%, respectively) (Supplementary Figs.…”

Section: Resultsmentioning

confidence: 99%

“…LYPD1 is a GPI-anchored membrane protein with medium-to-high cell surface expression in HGSOC. The expression of LYPD1 is limited to tissues of origin, such as the fallopian tube and anterior pituitary gland, making it a compelling TCB target for HGSOC 17 .…”

Section: Introductionmentioning

confidence: 99%

PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

Lee

Szvetecz

Polli

et al. 2021

Sci Rep

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High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

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“…T-BsAbs that target B7-H3, B7-H4, or B7-H6 have shown promising antitumor effects in mouse models against melanoma, breast cancer, and ovarian cancer, respectively [124][125][126]. Other distinctive target antigens include a lyase, a Wnt signaling regulator, an orphan receptor, and a sialylated cluster of differentiation (CD) antigen [57,[127][128][129]. Several T-BsAbs mentioned here are now in clinical trials for evaluation of their efficacy and safety.…”

Section: Preclinical Researchmentioning

confidence: 99%

T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

2021

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As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.

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Anti-LYPD1/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Ovarian Cancer

Cited by 8 publications

References 36 publications

T cell‐dependent bispecific antibodies alter organ‐specific endothelial cell–T cell interaction

T cell‐dependent bispecific antibodies alter organ‐specific endothelial cell–T cell interaction

PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

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