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Nervous System Diseases

Other Diseases

Congenital Disorders

Small molecule drug

Monoclonal antibody

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A glimpse into the focused therapeutic areas

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Targets

Most frequently developed targets

Disease Domain	Count

Nervous System Diseases	5
Endocrinology and Metabolic Disease	2
Immune System Diseases	1

Top 5 Drug Type	Count

Small molecule drug	4
Monoclonal antibody	1

Top 5 Target	Count

MAO-B(Monoamine oxidase B)	1
VMAT2(Synaptic vesicular amine transporter)	1
CGRP(Calcitonin gene-related peptide)	1

CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical.

Scientific ReportsQ3 · CROSS-FIELD

Interactions between LHX3- and ISL1-family LIM-homeodomain transcription factors are conserved in Caenorhabditis elegans

Q3 · CROSS-FIELD

ArticleOA

Author: Llamosas, Estelle ; Jacques, David A ; Dastmalchi, Siavoush ; Ripin, Nina ; Matthews, Jacqueline M ; Jeffries, Cy M ; Nicholas, Hannah R ; Bhati, Mugdha

AbstractLIM-Homeodomain (LIM-HD) transcription factors are highly conserved in animals where they are thought to act in a transcriptional ‘LIM code’ that specifies cell types, particularly in the central nervous system. In chick and mammals the interaction between two LIM-HD proteins, LHX3 and Islet1 (ISL1), is essential for the development of motor neurons. Using yeast two-hybrid analysis we showed that the Caenorhabditis elegans orthologs of LHX3 and ISL1, CEH-14 and LIM-7 can physically interact. Structural characterisation of a complex comprising the LIM domains from CEH-14 and a LIM-interaction domain from LIM-7 showed that these nematode proteins assemble to form a structure that closely resembles that of their vertebrate counterparts. However, mutagenic analysis across the interface indicates some differences in the mechanisms of binding. We also demonstrate, using fluorescent reporter constructs, that the two C. elegans proteins are co-expressed in a small subset of neurons. These data show that the propensity for LHX3 and Islet proteins to interact is conserved from C. elegans to mammals, raising the possibility that orthologous cell specific LIM-HD-containing transcription factor complexes play similar roles in the development of neuronal cells across diverse species.

Allergy, Asthma & Immunology ResearchQ2 · MEDICINE

Higher Binding Affinity and In Vitro Potency of Reslizumab for Interleukin-5 Compared With Mepolizumab

Q2 · MEDICINE

Article

Author: Pukac, Laurie ; Clarke, Adam W. ; Lyons, Jacquelyn ; Estephan, Tanya ; Doyle, Anthony ; Laine, David ; Mabon, David ; Husten, Jean ; Liddament, Mark

Reslizumab and mepolizumab are recently approved monoclonal antibodies for the treatment of severe (uncontrolled) eosinophilic asthma. Both are effective in neutralizing the function of interleukin-5 (IL-5). This study is the first to compare the binding affinity and in vitro potency of both antibodies in head-to-head assays. Two assays assessed binding affinity (using the equilibrium dissociation constant [K_D]) of each drug for human IL-5. In the Biacore surface plasmon resonance assay, the association constant (k_on) values for human IL-5 for reslizumab and mepolizumab were 3.93 × 10⁶ and 1.83 × 10⁵, respectively. The dissociation constant (k_off) values were 4.29 × 10⁻⁴ and 2.14 × 10⁻⁴, respectively. Calculated K_D values for human IL-5 for reslizumab and mepolizumab were 109 and 1,170 pM, respectively, representing an approximately 11-fold stronger binding affinity with reslizumab. In the Kinetic Exclusion Assay, the k_on values for human IL-5 for reslizumab and mepolizumab were 3.17 × 10⁶ and 1.32 × 10⁵, respectively. The k_off values were 1.36 × 10⁻⁵ and 1.48 × 10⁻⁵, respectively. Measured K_D values for human IL-5 for reslizumab and mepolizumab were 4.3 and 112 pM, respectively, representing an approximately 26-fold stronger binding affinity for reslizumab. A human-IL-5-dependent cell proliferation assay was developed to assess in vitro potency, based on a human cell line selected for enhanced surface expression of IL-5 receptor-alpha and consistent proliferation response to IL-5. The concentration at which 50% inhibition occurred (IC₅₀) was determined for both antibodies. Reslizumab and mepolizumab inhibited IL-5-dependent cell proliferation, with IC₅₀ values of approximately 91.1 and 286.5 pM, respectively, representing on average 3.1-fold higher potency with reslizumab. In conclusion, comparative assays show that reslizumab has higher affinity binding for and in vitro potency against human IL-5 compared with mepolizumab. However, these results do not take into consideration the different methods of administration of reslizumab and mepolizumab.

100 Deals associated with Teva Pharmaceuticals Australia Pty Ltd

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100 Translational Medicine associated with Teva Pharmaceuticals Australia Pty Ltd

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Pipeline

Pipeline Snapshot as of 15 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Approved

5

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Edaravone	Amyotrophic Lateral Sclerosis More	Approved
Rasagiline mesylate ( MAO-B )	Parkinson Disease More	Approved
Deutetrabenazine ( VMAT2 )	Tardive Dyskinesia More	Approved
Glatiramer Acetate	Multiple Sclerosis, Relapsing-Remitting More	Approved
Fremanezumab-VFRM ( CGRP )	Migraine Disorders More	Approved