Engineered bispecific antibodies targeting the interleukin-6 and -8 receptors potently inhibit cancer cell migration and tumor metastasis

Hui-lin, Yang; Karl, Michelle; Wang, Wentao; Starich, Bartholomew; Tan, Haotian; Kiemen, Ashley; Pucsek, Alexandra B.; Russo, Gabriella; Pan, Tim; Jaffee, Elizabeth M.; Fertig, Elana J.; Wirtz, Denis; Spangler, Jamie B.

doi:10.1016/j.ymthe.2022.07.008

Cited by 13 publications

(40 citation statements)

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“…The association rates for binding to IL-6R and IL-8R are very close in value, and there is not a substantial difference in the monovalent binding domain affinities for either receptor [Table 4], as was observed experimentally [28]. Moreover, the calculated monovalent affinities are consistent with the results from the experimental characterization of BS1 [Table S2] [28]. The second binding step, where the binary antibody-receptor complex cross-links with an additional receptor to form a ternary receptor-antibody-receptor complex, is substantially faster than the initial binding.…”

Section: Best-fit Parameters Recapitulate Experimental Observationsmentioning

confidence: 80%

Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors

Ray,

Yang,

Spangler

et al. 2023

Preprint

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The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.

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Section: Best-fit Parameters Recapitulate Experimental Observationsmentioning

confidence: 80%

Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors

Ray,

Yang,

Spangler

et al. 2023

Preprint

Self Cite

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“…Additional knowledge about the role of cytokines and their role in the tumor formation, progression and recurrence of bladder cancer will be critical to inform clinical management and new therapeutic approaches. 46…”

Section: Discussionmentioning

confidence: 99%

“…However, a large longitudinal study is required to statistically eliminate confounding factors and support this theory. Additional knowledge about the role of cytokines and their role in the tumor formation, progression and recurrence of bladder cancer will be critical to inform clinical management and new therapeutic approaches 46 …”

Section: Discussionmentioning

confidence: 99%

Urinary IL‐6 and IL‐8 as predictive markers in bladder urothelial carcinoma: A pilot study

VandenBussche,

Heaney,

Kates

et al. 2023

Cancer Cytopathology

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BackgroundCytokines are known to be a key a factor in numerous malignancies and to exert an important regulatory role in the tumor microenvironment. Interest has grown in understanding how cytokines modulate the tumor microenvironment and which cytokines may serve as markers of the tumor process; however, a complete picture of the cytokine landscape in bladder cancer remains unclear.MethodsFresh urine specimens with sufficient volume were collected at random intervals. The urine concentrations of IL‐8 (CXCL8), CCL18, and CXCL9 were determined using the standard commercially available enzyme immunoassay. The urine concentrations of IL‐6 were determined using the high sensitivity enzyme immunoassay kit. Urinary cytokine concentrations were normalized with urinary creatinine concentrations.ResultsSignificantly elevated concentrations of IL‐6 and IL‐8 were detected in the urine from patients with urothelial carcinoma on follow‐up compared to patients with benign follow‐up. The presence of both IL‐6 and IL‐8 in the urine samples from the high grade urothelial carcinoma (HGUC) cohort revealed a clear discrimination when compared to samples from patients with benign follow‐up. The presence of the combination of both IL‐6 and IL‐8 had a sensitivity of 90.0% and a specificity of 81.25%. Similar data were obtained when receiver operating characteristic analysis was performed on both IL‐6 and IL‐8 concentrations in the urine from patients with HGUC vs. the hematuria cohort.ConclusionsThe presence of IL‐6 and IL‐8 in urine specimens may have predictive value for urothelial carcinoma. However, a large longitudinal study is required to statistically eliminate confounding factors and support this theory.

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“…[18][19][20] Using bispecific antibodies (BsAbs) to target TNF-α and IL-23p19 simultaneously has emerged as a promising strategy to improve therapeutic efficacy and simplify combinatorial therapy for IBD. 21,22 BsAbs has primarily been used in oncology, [23][24][25][26] recent research has demonstrated that the bispecific antibody Amivantamab exhibits long-lasting and sustained remission in the management of non-small cell lung cancer (NSCLC) with cEGFR mutations, marking a significant breakthrough in cEGFRmutated NSCLC therapy. 27 However, the potential of BsAb in IBD clinical applications to enhance therapeutic efficacy is foreseeable.…”

Section: Schematic Illustration Of Engineering a Bispecific Nanobody-...mentioning

confidence: 99%

Novel bispecific nanobody mitigates experimental intestinal inflammation in mice by targeting TNF‐α and IL‐23p19 bioactivities

Wang,

Kang,

et al. 2024

Clinical & Translational Med

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BackgroundInflammatory bowel diseases (IBDs) pose significant challenges in terms of treatment non‐response, necessitating the development of novel therapeutic approaches. Although biological medicines that target TNF‐α (tumour necrosis factor‐α) have shown clinical success in some IBD patients, a substantial proportion still fails to respond.MethodsWe designed bispecific nanobodies (BsNbs) with the ability to simultaneously target human macrophage‐expressed membrane TNF‐α (hmTNF‐α) and IL‐23. Additionally, we fused the constant region of human IgG1 Fc (hIgG1 Fc) to BsNb to create BsNb‐Fc. Our study encompassed in vitro and in vivo characterization of BsNb and BsNb‐Fc.ResultsBsNb‐Fc exhibited an improved serum half‐life, targeting capability and effector function than BsNb. It's demonstrated that BsNb‐Fc exhibited superior anti‐inflammatory effects compared to the anti‐TNF‐α mAb (infliximab, IFX) combined with anti‐IL‐12/IL‐23p40 mAb (ustekinumab, UST) by Transwell co‐culture assays. Notably, in murine models of acute colitis brought on by 2,4,6‐trinitrobenzene sulfonic acid（TNBS) and dextran sulphate sodium (DSS), BsNb‐Fc effectively alleviated colitis severity. Additionally, BsNb‐Fc outperformed the IFX&UST combination in TNBS‐induced colitis, significantly reducing colon inflammation in mice with colitis produced by TNBS and DSS.ConclusionThese findings highlight an enhanced efficacy and improved biostability of BsNb‐Fc, suggesting its potential as a promising therapeutic option for IBD patients with insufficient response to TNF‐α inhibition.Key points A bispecific nanobody (BsNb) was created to target TNF‐α and IL‐23p19, exhibiting high affinity and remarkable stability. BsNb‐Fc inhibited the release of cytokines in CD4+T cells during co‐culture experiments. BsNb‐Fc effectively alleviated colitis severity in mouse model with acute colitis induced by DSS or TNBS, outperforming the IFX&UST combination.

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Engineered bispecific antibodies targeting the interleukin-6 and -8 receptors potently inhibit cancer cell migration and tumor metastasis

Cited by 13 publications

References 100 publications

Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors

Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors

Urinary IL‐6 and IL‐8 as predictive markers in bladder urothelial carcinoma: A pilot study

Novel bispecific nanobody mitigates experimental intestinal inflammation in mice by targeting TNF‐α and IL‐23p19 bioactivities

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