Creative Biolabs features a superior antibody engineering platform for developing novel bispecific antibodies (BsAb) for the therapy of receptor signaling interference in lung and respiratory illnesses.
Pulmonary and respiratory diseases vary from the common cold, influenza, and pharyngitis to potentially fatal conditions such as bacterial pneumonia, acute asthma, and lung cancer. Abnormal immune reactions, excessive inflammation, and/or a disordered wound-healing process cause or worsen a variety of pulmonary and respiratory disorders. For example, Th2 and Th17 polarized immune responses, are the primary mediators of allergic asthma; severe neutrophilic asthma is caused by T-cell and ILC3 production of IL17A/F and IL22 (RORc-dependent); and idiopathic pulmonary fibrosis, a progressive fibrotic disease of the lungs, has been identified to be caused by an abnormal wound healing process and associated inflammation in the pulmonary interstitium.
Fig.1 In asthma, eosinophilic airway inflammation is caused by two distinct routes.1
The use of therapeutic antibodies to treat lung cancer and asthma is a breakthrough that opens up new avenues for the treatment of respiratory disorders. However, due to biological redundancy, cells frequently have escape paths. As BsAbs are bispecific, they can be used to simultaneously target a primary target and an escape pathway, or to block the same pathway in two locations, enhancing therapeutic efficacy.
BsAbs that inhibit proinflammatory cytokines or fibroblast factors can alleviate or even cure pulmonary and respiratory illnesses. In a preclinical in vivo model, an IgG-like T-cell engaging bispecific antibody (ITE) targeting DLL3 and CD3 can cause purely DLL3-dependent T-cell guided lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues, resulting in small cell lung cancers (SCLC) regression². Furthermore, a bispecific single-domain antibody that can bind two highly conserved regions on a single SARS-CoV-2 variant's Omicron receptor-binding domain is shown to be effectively delivered to the lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections³. BsAbs targeting IL-4R and IL-5, as well as a combination of monospecific antibodies, have been shown to reduce eosinophilia, IgE production, goblet cell metaplasia, and bronchial hyperreactivity in asthma patients.
| Paper Title | A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors |
| Journal | Cancer Research |
| Published | 2016 |
| Abstract | Resistance to tyrosine kinase inhibitors (TKI) develops in non-small cell lung malignancies (NSCLC) with activating EGFR mutations, typically through second-site EGFR mutations (T790M) and/or cMet pathway activation. The team of researchers designed a bispecific EGFR-cMet antibody with various mechanisms of action that inhibit both primary and secondary EGFR mutations as well as the cMet pathway. The EGFR-cMet BsAb inhibits EGFR and cMet phosphorylation as well as phospho-ERK and phospho-AKT more efficiently than a combination of single receptor-binding antibodies. The EGFR-cMet BsAb therapy reduces tumor growth in NSCLC tumor models driven by EGFR and/or cMet by downregulating signaling/receptors and interacting with Fc-mediated effectors. |
| Result |
A bispecific EGFR-cMet antibody is demonstrated to inhibit tumors with primary EGFR-activating mutations, tumors with the T790M second-site resistance mutation in EGFR, and tumors with cMet pathway activation. Furthermore, the combination of an EGFR-cMet BsAb and a third-generation EGFR TKI results in complete and long-term tumor remission. Interestingly, EGFR-cMet BsAb therapy of cynomolgus monkeys results in no toxicities, including the absence of skin rash seen with other EGFR-directed medicines. This preliminary research implies that an EGFR-cMet BsAb for patients with lung cancer and other malignancies linked with abnormal EGFR and cMet signaling could be created.
Fig.2 EGFR-cMet BsAb caused tumor cell lysis through enhanced effector function.4 |
Creative Biolabs rises to the top of the BsAb services market after years of hard labor. We offer professional services for developing various formats of BsAbs to treat pulmonary and respiratory disorders.
References
1. Brusselle, Guy G et al. "Eosinophils in the spotlight: Eosinophilic airway inflammation in nonallergic asthma." Nature Medicine vol. 19,8 (2013): 977–979.
2. Hipp, Susanne, et al. "A bispecific DLL3/CD3 IgG-like T-cell engaging antibody induces antitumor responses in small cell lung cancer." Clinical Cancer Research 26.19 (2020): 5258-5268.
3. Yuan, Mengqi, et al. "A bispecific antibody targeting RBD and S2 potently neutralizes SARS-CoV-2 Omicron and other variants of concern." Journal of Virology 96.16 (2022): e00775-22.
4. Moores, Sheri L et al. "A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors." Cancer research vol. 76,13 (2016): 3942-53.
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