Talks covered ADC architecture, especially new linker chemistry and site-specific conjugation, as well as therapeutic index, stability, next generation cytotoxins and mechanism of action, heterogeneity, aggregation, analytical characterization, process development and critical quality attributes especially with respect to formulation.
The ADC lexicon used by Hans-Peter Gerber, Executive Director, Bioconjugates R&D, at Pfizer Oncology Research Unit East, was “empowered antibodies” and “therapeutic index”. The empowerment bestowed upon the antibody was its payload, or warhead as some would refer to it in other talks, which it delivered to the targeted cell with its surface displayed antigen. The therapeutic index was the score card, focus or indicator for improvement and as such was the key driver to innovation; the index being the dosage ratio of maximum tolerability to minimum efficacy. Some of the innovation at Pfizer presented by Gerber included methods for site-specific conjugation of the payload to the antibody which the audience would soon realize was going to be a common theme in talks to come. Site-specific conjugation was highlighted for its facilitation of CMC and regulatory filings presumably because it resulted in the advancement to a second generation ADC that was less heterogeneous. Gerber also talked about innovative empowerment and improved therapeutic index by listing a couple strategies to target cancer such as a focus on tumor initiating cells and payloads with cell cycle dependent and independent mechanisms of action.
Sutro Biopharma gave three presentations, those being by Senior Directors Dawn Benson of Quality and Heidi Hoffmann of Manufacturing, and Chief Scientific Officer Trevor Hallam. The protein synthesis platform developed and commercialized by Sutro is a “disruptive” and “game changing” technology in the biopharmaceutical industry, which is a cell-free system known as Xpress CF based on the E. coli-based open cell-free synthesis technology pioneered by Professor James Swartz at Stanford University. Xtract DF is derived from Xpress CF and was described as the protein synthesis “secret sauce” behind the unique platform. The open system offers a “large parameter space” for optimization of the first stage of the process life cycle in a high throughput format which has been proven to be linearly scalable from the 250 L to 100 L scale as far as volumetric activity of active target protein in g/L yield. Sutro gets frequent flier mileage out of the marketing statement, “gene sequence to drug substance in days”, used to describe the speed of their technology. Site-specific conjugation practically anywhere on the antibody is achieved by incorporation of an unnatural amino acid into the protein sequence via an amber codon and a tRNA and aminoacyl-tRNA synthetase pair for linkage to the payload via click chemistry. The platform essentially gives Sutro combinatorial synthesis capability to screen for an optimal ADC architecture for therapy with any antibody at any position with variable linkers and payloads. In fact, game changer status is taken to a new height in oncology therapy since the ADC architecture optimization capability includes the ability to create next generation bi-specific and multi-specific antibodies such that one ADC can include more than one type of payload. This was explained by describing the initial and separate translation of light chain with incorporation of a site-specifically located unnatural amino acid followed by heavy chain with incorporation of a different orthogonally reactive site-specifically located unnatural amino acid.
Tim Lowinger, CSO of Mersana Therapeutics, presented on the Fleximer platform, which is built on a biodegradable polyacetal polymer which can be conjugated to the antibody via either cysteine or lysine residues. The Fleximer platform is advantageous because it acts as a solubilization vehicle for hydrophobic drugs, is enabling for low potency drugs as well as low normal expression tumor surface antigen due to its high payload capacity whilst still having good pharmacokinetic properties, has a broad array of linker chemistries to accommodate a variety of payloads, and has a stabilizing effect as an anti-aggregation agent. Fleximer has especially found utility in conjugation to antibody fragments since its polymer synthesis can be engineered to optimize stability and preserve critical quality attributes of the ADC by matching its size relative to the antibody fragment.
Another company in the line-up of presentations was ImmunoGen, who gave several talks, including by Michael Miller, Principle Scientist in Chemistry, and Rajeeva Singh, Lead Scientist in ADC Technology Development, plus chaired more than one topic track session. ImmunoGen has broadened the therapeutic spectrum of ADC’s by expanding the mechanism of action beyond inhibition of tubulin polymerization to include DNA-acting agents. They reported on advances in the development of their IGN payload platform which contain indolino benzodiazepine dimers responsible for sequence selective DNA alkylation and cross-linking adduct formation with high potency as determined by in vitro IC50 values in the picomolar range. The therapeutic index was improved by making certain modifications to limit the mechanism of action to either DNA alkylating or cross-linking. ImmunoGen also generated results which were an indication that linker selection in ADC design played a role in the therapeutic index of the IGN family of agents. ImmunoGen has also observed that linker development and selection can play a role in combating the mechanism of tumor cell multidrug resistance apparently by increasing the residence time of the ADC and payload inside the cell versus being exported back outside. Other desired features of ImmunoGen’s IGN-based ADC platform include good aqueous solubility and stability. ImmunoGen also reported on advances in linker design which expanded the therapeutic opportunity of their maytansinoid ADC (MAY-ADC or AMC) platform. The working hypothesis derived from results thus far is that their CX-AMC platform (CX indicates a new tri-glycyl peptide segment added-on to their cleavable disulfide linker) enables target cell-activated killing of bystander cells in a heterogeneous tumor cell population (i.e., antigen-positive and antigen-negative) via enhanced linker processing resulting in formation of a potent CX-MAY catabolite with improved efficiency in lysosomal processing with respect to extracellular efflux.
In summary, it became ever increasingly evident that ADC architectural design and screening for optimized therapeutic index must involve an integrated approach, or perhaps more aptly described as a combinatorial approach, involving all aspects of each component; in other words, a combinatorial approach should include; 1) antigen selection and management of DAR, location and heterogeneity by site-specific conjugation such as by engineered cysteines or site-specific incorporation of unnatural amino acids for the antibody, 2) cleavable and noncleavable linkage chemistry coupled with modifications for enhanced intracellular processing, for example with respect to multidrug resistance for the linker format, and 3) multiple mechanisms of action for the payload whether it be tubulin-acting, DNA-acting, or inhibition of RNA polymerase. Manufacturing was also a topic of some talks; in fact, the last speaker of the conference, Klaus Kaiser, Head of Downstream Processing and Analytical at Bayer Pharma AG, left the audience with some thoughts about the ADC community’s need for a one-stop shop CMO and the next major improvement or breakthrough in ADC’s possibly being continuous manufacturing involving plug-flow or continuous stirred tank reactors. Ironically, a market research report had been released earlier in the conference that was titled, Antibody Drug Conjugates: Contract Manufacturing Market 2014 – 2024.
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