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FDA Feedback: Regulatory Guidance and Expectations for Next Generation Protein Therapeutics and Bioconjugates
H. Kaspar Binz, Ph.D.
Next Generation Oncology Biologics
Molecular Partners AG
FDA Feedback: Regulatory Requirements
Next Generation Protein Therapeutics Translation from Discovery to the Clinic: Lessons Learnt from Preclinical and Clinical Studies
The ADCs as cancer therapeutics have gained significant momentum in last few years with over 60 ADCs in clinical development. While this is highly encouraging development, it is also noted that nearly 90% of ADC molecules have failed in clinical trials either due to high toxicities or very poor clinical activity. There is also high failure rate of ADCs in preclinical development as well. The presentation would review some common themes on failures and risk mitigation strategies to reduce the failure rate of ADCs and increase the clinical success.
The requirements of multi-functional oncology treatment match perfectly well with the strengths of the designed ankyrin repeat protein platform. With the successful first systemic validation of the platform by the oncology candidate MP0250, a dual VEGF/HGF inhibitor, we now are enabled to walk new avenues for cancer treatment. I will highlight these avenues in my presentation using preclinical and the most recent clinical data on novel therapeutic concepts for clinical oncology.
We developed a new ADC technology with the derivative of DX-8951 which is a novel DNA topoisomerase I inhibitor. Our ADC technology has seven unique features; novel payload, high potency, bystander effect, high clearance of the payload, stable linker, tumor selective cleavage, and high DAR. I will review this ‘smart chemo’ ADC technology and introduce some updates on ADC programs of Daiichi Sankyo.
Targeting PD-L1-overexpressing cells with therapeutic antibodies is a clinically validated strategy for the treatment of multiple solid tumors. In order to increase efficacy, PD-1/PD-L1 blocking agents are currently being tested in combination with additional immune checkpoint modulators (ICMs). However, such combination therapies are associated with considerable treatment-related adverse events, resulting in a narrow therapeutic window and thereby limiting treatment efficacy. To maximize potency and improve the safety of ICM combination approaches, we designed a multi-specific molecule bearing two ICM domains that depletes PD-L1-overexpressing cancer cells via selective recruitment and stimulation of tumor-reactive effector T cells in the tumor microenvironment. The multi-specific antibody format potently blocks PD-L1/PD-1 signaling and elicits further T cell activation through its costimulatory domain solely in the presence of cells that overexpress PD-L1. In an HCC827 xenograft model in hPBMC-supplemented NOG mice, the tri-specific strongly slowed tumor growth and enhanced intratumoral CD8+ T cell activation to a greater extent than monospecific IgG variants of the anti-PD-L1 and anti-costimulatory receptor domains.
Affimer therapeutics are based on the human protein Stefin A, a small intracellular protease inhibitor. Using phage display we have generated highly selective Affimer binders to range of therapeutic targets. These molecules have then been fused to either the Fc domain or to a full antibody to create bispecific molecules that express and are able to engage both target antigens.
Teneobio’s discovery platform utilizes VH domains of fully human heavy chain antibodies (UniAbs) to develop bi-, tri-, and tetravalent antibodies. Binding domains of UniAbs are stable structures that can be easily put together into multi-specific antibodies. Clinical trials of Teneobio’s first tri-valent antibody will be initiated in 2018.
Overcoming Delivery Challenges and the Blood Brain Barrier
The blood-brain barrier (BBB) limits exposure of large molecules to the central nervous system, but recent advances in utilizing natural BBB receptors to transport biotherapeutics into the brain have offered promise for treating neurological disorders. We describe the engineering and properties of the Antibody Transport Vehicle (ATV), a BBB-targeting engineered Fc platform that can deliver therapeutic concentrations of proteins into the brain.
Addressing Challenging Targets with Next Generation Protein Therapeutics