Author: Molvi, Zaki ; Dao, Tao ; Klatt, Martin G ; White, Thomas E ; Lorenz, Ivo C ; O'Reilly, Richard J ; Korontsvit, Tatyana ; Mun, Sung Soo ; Nyakatura, Elisabeth K ; Balderes, Paul J ; Pohl, Mary Ann ; Khan, Abdul G ; Scheinberg, David A

Phosphopeptides derived from dysregulated protein phosphorylation in cancer cells can be processed and presented by MHC class I and class II molecules and, therefore, represent an untapped class of tumor-specific antigens that could be used as widely expressed "public" cancer neoantigens (NeoAgs). We generated a TCR mimic (TCRm) mAb, 6B1, specific for a phosphopeptide derived from insulin receptor substrate 2 (pIRS2) presented by HLA-A*02:01. The pIRS2 epitope's presentation by HLA-A*02:01 was confirmed by mass spectrometry. The TCRm 6B1 specifically bound to pIRS2/HLA-A2 complex on tumor cell lines that expressed pIRS2 in the context of HLA-A*02:01. Bispecific mAbs engaging CD3 of T cells were able to kill tumor cell lines in a pIRS2- and HLA-A*02:01-restricted manner. Structure modeling shows a prerequisite for an arginine or lysine at the first position to bind mAb. Therefore, 6B1 could recognize phosphopeptides derived from various phosphorylated proteins with similar amino acid compositions. This raised the possibility that a TCRm specific for the pIRS2/HLA-A2 complex could target a range of phosphopeptides presented by HLA-A*02:01 in various tumor cells. This is the first TCRm mAb to our knowledge targeting a phosphopeptide/MHC class I complex; the potential of this class of agents for clinical applications warrants further investigation.

01 Jun 2021·VirologyQ3 · MEDICINE

A human bispecific neutralization antibody against four serotypes of dengue virus

Q3 · MEDICINE

Article

Author: Yu, Yunzhou ; Chen, Lei ; Lu, Jiansheng ; Yang, Zhixin ; Wang, Rong

In tropical and subtropical countries, dengue virus (DENV) infections have been increasing; however, we still lack effective therapy. In the present study, we aimed to engineer a bispecific antibody (subsequently named LUZ-8F2-6B1), based on monoclonal antibody 6B1, which has anti DENV-1, 2, and 3 activity, and 8F2, which has anti DENV-4 activity. LUZ-8F2-6B1 displayed potent neutralization activity against four serotypes of DENV by binding to the envelop protein. In vivo, we demonstrated that LUZ-8F2-6B1 could provide protection against infection by four serotypes of DENV in a mouse model. In addition, the deletion of nine amino acids in the Fc region (LUZ-8F2-6B1-9del) completely abolished the antibody-dependent enhancement observed at lower doses of the antibody. Thus, LUZ-8F2-6B1 is a promising, safe, and effective agent for the prophylaxis and treatment of DENV infection.

01 Apr 2021·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Structural modifications on indole and pyrimidine rings of osimertinib lead to high selectivity towards L858R/T790M double mutant enzyme and potent antitumor activity

Q3 · MEDICINE

Article

Author: Liu, Qiao ; Chen, Chen ; Li, Zerui ; Fang, Lei ; Luo, Yanli

EGFR inhibitors represent a significant milestone for treatment of non-small cell lung cancer, however, they suffer from the acquired drug resistance. Utilizing osimertinib as the lead compound, this work has explored the structural modifications on the indole and pyrimidine rings of osimertinib to generate novel osimertinib derivatives. The in vitro enzymatic and cellular studies showed that the derivatives possessed high selectivity towards double mutant EGFR and potent antitumor activity. Particularly, compound 6b-1, the most active compound, exhibited excellent inhibitory activity against double mutant EGFR (IC₅₀ = 0.18 nM) and wild-type EGFR (IC₅₀ = 2.89 nM) as well as H1975 cells (IC₅₀ = 1.44 nM). Western blot analysis showed that 6b-1 completely inhibited double mutant EGFR and Erk phosphorylation. In vivo test using xenograft model indicated that compound 6b-1 had better antitumor efficacy than osimertinib. More importantly, 6b-1 displayed many advantages in the pharmacokinetic study, including better oral bioavailability and metabolism character.

100 Deals associated with Lerdelimumab

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KEGG	Wiki	ATC	Drug Bank
-	Lerdelimumab	-	DB06557

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Indication	Highest Phase	Country/Location	Organization	Date
Cataract	Phase 3	-	Cambridge Antibody Technology	-
Cataract	Phase 3	-	Genzyme Corp.	-
Cicatrix	Phase 3	ZA	Cambridge Antibody Technology	-
Cicatrix	Phase 3	-	Cambridge Antibody Technology	-
Cicatrix	Phase 3	US	Cambridge Antibody Technology	-
Cicatrix	Phase 3	-	Genzyme Corp.	-
Vitreoretinopathy, Proliferative	Phase 3	-	Genzyme Corp.	-
Vitreoretinopathy, Proliferative	Phase 3	GB	Cambridge Antibody Technology	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ARVO2004	Phase 2	Cicatrix	56	Trabio	(tpclvtsbgx) = Events coded to 'Eye Disorders' were the most common, comprising 84% of all events; and of these the most common were in the 'Ocular Infections, Irritations and Inflammations' category with 14% Trabio patients and 25% of the placebo patients reporting one or more events ftoigbsnpw (sltwiztbwo )	Positive	01 May 2004
				Placebo
CAT-152 (ARVO2003)	Not Applicable	TGFß2	-	CAT-152 (100µg)	(tpurtlezsf) = udskqdhlzb ipjgeuhxbn (phwznzhvii ) View more	Positive	01 May 2003
				Placebo (phosphate buffered saline)	(yhfalvsybs) = peebtauzbs jgivtbljlk (dmqhzuybqa )
ARVO2003	Not Applicable	Blister Maintenance	27	CAT-152	(oyunypvrgb) = 5-FU caused corneal epitheliopathy (p=0.003) czsgrhwgfx (lwvijbvjxq )	-	01 May 2003
				5-FU
ARVO2002	Not Applicable	-	54	CAT-152 (1mg/ml)	(rnrlchpcrd) = ycwadicdqj vbriuthejs (yqktzmjfmj )	-	01 Dec 2002
				5-fluorouracil (5-FU) (50mg/ml)	(rnrlchpcrd) = uledylfego vbriuthejs (yqktzmjfmj )

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