Translational Success in Parkinsons Disease

Offspring Biosciences operated as an extension of BioArctic’s scientific team by integrating our adapted version of aspects of AstraZeneca’s 5R Framework (Right Target, Right Tissue, Right Safety) into their development cycle. This collaboration leveraged the Tissue Insights™ platform across four of our five key operational modules:
 

Antibody Selection and Optimization                               [Module 2]

 

The Task:  Screen a pool of lead antibody candidates to identify the optimal binder.
 

The Offspring Approach:  As an alternative to relying on synthetic binding arrays, Offspring established an effective screening workflow using post-mortem human brain sections from non-disease affected individuals and confirmed PD cases.
 

The Outcome:  This "Tissue-First" screening approach filtered out candidates that bound
well in silico but failed to engage pathology in situ. Exidavnemab emerged as the lead
candidate, demonstrating superior binding profiles to pathological structures
compared to competitors.

Target Engagement, Specificity Profiling & Biological Effect [Module 3]
 

The Task: Prove that Exidavnemab engages alpha-synuclein and differentiates between
toxic aggregates and healthy monomers in human tissue.

The Offspring Approach:
        Human Validation: We utilized advanced Immunohistochemistry (IHC) and in situ Proximity Ligation Assay (isPLA) to demonstrate selective target engagement in human brain samples with toxic deposits of alpha-synuclein.
        In Vivo Translation: Highly sensitive IHC assays demonstrated brain penetrance and selective engagement after in vivo administration of Exidavnemab in a mouse model.
        Efficacy Quantification: This was extended by demonstrating pharmacological efficacy in reducing synuclein deposits in treated mice, using quantitative AI-assisted image analysis to generate robust statistical datasets.
        The Mechanism Check: We compared Exidavnemab against competitors antibodies to benchmark selectivity.

 

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Safety Evaluation                                                            [Module 4]     
 

The Task:  De-risk the asset regarding on- and off-target binding in tissue sections from human organs.
 

The Offspring Approach:  As support to the execution of a full TCR (Tissue Cross-Reactivity) study run by a secondary, GLP-certified, CRO laboratory, we transferred and assisted in the set-up and optimization of the IHC assay with the Exidavnemab antibody. This assay was finally applied to evaluate the antibody’s binding characteristics on a multi-organ Tissue Microarrays (TMAs) in alignment with FDA guidelines, as means to identify potential safety liabilities.

 

Patient Selection and Indication Expansion                       [Module 5]
 

The Task: Patient stratification for therapuetic indications beyond Parkinsons Disease.
 

The Offspring Approach: We performed IHC staining with the Exidavnemab antibody on a curated cohort of donor tissues from patients afflicted by Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and Multiple System Atrophy (MSA).
      While synucleopathic disorders like PD, PDD and DLB are characterized by intraneuronal inclusions of fibrillar alpha-synuclein deposits, including Lewy bodies, MSA is defined by Glial Cytoplasmic Inclusions (GCIs) of alpha-synuclein in oligodendrocytes.
 

The Outcome: Offspring demonstrated that Exidavnemab robustly stains in the above disorders, including GCIs in the cerebellum and putamen of MSA patients. This confirmed that the antibody targets the specific pathological aggregates relevant to MSA, providing the biological rationale to expand the Phase 2a clinical program targeting patients PD patients with a follow up Phase 2b program focused on MSA patients.