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

被引:2
|
作者
Ray, Christina M. P. [1 ,2 ,3 ]
Yang, Huilin [4 ,5 ]
Spangler, Jamie B. [1 ,4 ,5 ,6 ,7 ,8 ,9 ]
Mac Gabhann, Feilim [1 ,3 ,10 ]
机构
[1] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21218 USA
[2] Johns Hopkins Univ, Sch Med, Med Scientist Training Program, Baltimore, MD 21218 USA
[3] Johns Hopkins Univ, Inst Computat Med, Baltimore, MD 21218 USA
[4] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD USA
[5] Johns Hopkins Univ, Sch Med, Translat Tissue Engn Ctr, Baltimore, MD USA
[6] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD USA
[7] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA
[8] Johns Hopkins Univ, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD USA
[9] Johns Hopkins Sch Med, Dept Ophthalmol, Baltimore, MD USA
[10] Johns Hopkins Univ, Inst Nano Biotechnol INBT, Baltimore, MD USA
基金
美国国家科学基金会;
关键词
IN-VITRO; ANTIGEN-EXPRESSION; DETAILED BALANCE; IL-8; RECEPTOR; BINDING; CANCER; AFFINITY; BIVALENT; KINETICS; THERAPY;
D O I
10.1371/journal.pcbi.1012157
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
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页数:35
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