Precision protein engineering to target oncology
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ADVERTISEMENT FEATURE ADVERTISER RETAINS SOLE RESPONSIBILITY FOR CONTENT Sutro Biopharma www.sutrobio.com Precision protein engineering to target oncology Sutro Biopharma combines its powerful cell-free protein synthesis platform with click chemistry to develop precisely engineered bioconjugate therapeutics for oncology. Sutro Biopharma, a drug development and manu- facturing company headquartered in South San Francisco, is transforming biotherapeutics discovery with a novel platform for cell-free protein synthesis combined with site-specific conjugation to non- natural amino acids (nnAAs), which together allow for the precise design and rapid expression of homogeneous therapeutic bioconjugates (Fig. 1). XpressCF: the power of going cell-free Designing and producing complex proteins using cell-based systems is expensive and time-consum- ing, often taking years from concept to clinic. Sutro reinvented this process using a cell-free platform, XpressCF, to produce discovery proteins consistently and quickly, allowing for the screening of thousands of variants of a molecule to get to an optimized lead. Core to XpressCF is Sutro’s proprietary cell-free extract manufactured from a highly engineered bacte- rial cell line, which contains all the transcriptional and translational machinery needed to rapidly express any desired protein from an encoding plasmid. The synthesis of proteins with XpressCF can be achieved overnight and does away with the need to make a new cell line for every new molecule, as required in tradi- tional cell-based expression systems. With protein expression reduced to a liquid-handling operation and the ability to produce and screen thousands of pro- tein variants in parallel overnight reactions, the drug discovery process is greatly sped up and simplified. Sutro’s complementary XpressCF+ platform fur- ther augments the cell-free process by incorporat- ing nnAAs at specific sites as a chemical handle to attach payloads selectively via highly efficient click chemistry conjugation. This capability enabled Sutro to create highly optimized clinical-stage anti- body–drug conjugates (ADCs), bispecific ADCs and early-stage immunostimulatory ADCs. The process leaves natural amino acids unmodified—resulting in a homogeneous and well-controlled drug product. The combination of the two platform technologies allows Sutro to screen many variants with different positioning of nnAAs in the protein sequence, permit- ting empirical identification of the optimal molecule. “Sutro’s XpressCF technology uses a proprietary cellular extract, which is a key element that guar- antees robust protein manufacturing,” said Trevor Hallam, CSO of Sutro. “That, in combination with our ability to make a single homogenous therapy, sets our technology apart—not only from a drug development standpoint, but also in our ability to supply the therapy needed to power our clinical trials without cell-based limitations.” The ability of Sutro’s platform to selectively conju- gate payloads precisely at specific sites in proteins is key to overcoming a problem that besets other approaches: heterogeneity in a single drug. Standard approaches, in which payloads are conjugated to nat- ural amino acids, lack control over the exact location of conjugation and how many payloads are added to each protein, resulting in a drug product that is a mixture of a number of different protein conjugates. By contrast, for Sutro, the end result is a precisely engineered, fully optimized and homogeneous drug product, which Sutro believes translates to a broader therapeutic window and better patient outcomes. “Sutro is working to address unmet needs by developing targeted therapies that can evolve with ever-changing cancer cells,” said Bill Newell, CEO of Sutro. “Our technology enables precision and speed.” Amongst Sutro’s pipeline are four unique ADCs. STRO-002 is an ADC targeting folate receptor-α with four cleavable hemiasterlin linker-warheads per antibody currently in phase 1/1b in advanced ovarian cancers. STRO-002 has shown good patient toler- ability with no ocular toxicity and a potentially better therapeutic index than other ADCs in development for ovarian and endometrial cancers. STRO-001, an ADC targeting CD74 with two non-cleavable may- tansinoid linker-warheads, is currently in phase 1a studies for lymphomas and multiple myeloma. While STRO-001 continues in dose escalation, it has shown signs of an improved therapeutic index versus other ADCs in hematological cancers and also exhibits no ocular toxicity. In collaboration with Bristol Myers Squibb, CC-99712, an ADC against B cell matura- tion antigen, is being studied in phase 1/1b trials for multiple myeloma, and, in a separate collaboration with Merck KGaA, (operating as EMD Serono in the US and Canada), M1231, a bispecific ADC that targets MUC1 and EGFR, is in phase 1/1b trials for non-small-cell lung cancer and esophageal cancer. Additional drug candidates enabled by Sutro’s platform currently in development are cytokine derivatives, in collaboration with Merck & Co., and a 24-valent Pneumococcal conjugate vaccine being developed by its spinout, Vaxcyte, Inc. Sutro has established the world’s only cell-free pro- tein production GMP facility in San Carlos, California, which can produce engineered proteins of consistent quality at scale and provide drug material through clinical development. Recently, dry powder formula- tions of the cell-free extract have further optimized the manufacturing process, enabling large-scale extract production with ease of shipping and flex- ibility of use for future product commercialization. Moving forward Sutro seeks to expand its partnerships with pharma- ceutical companies, whose long-standing expertise in disease biology has synergistically combined with the power of Sutro’s differentiating biologic design, discovery and manufacturing technology. “Our ultimate goal is to leverage these powerful collaborations to create best-in-class therapeutics and help fill the unmet needs of cancer patients with more targeted therapies”, said Newell. Conjugated antibody Cytokine derivative Bispecific antibody Cytokine Releasable mask Drug properties Structure Optimized format and affinity; improved specificity for optimized therapeutic window ISAC: Immune- stimulating ADC: targeting novel payloads Site-specific dual drug conjugate with complementary modalities (TME modulator ± immune modulator) Masked cytokine derivative ADC or ISAC Immune cell engager iADC Modality Bispecific ADC Tumor or stromal antigen Tumor antigen Tumor selective mask Tumor antigen Immune cell engager Target Dual tumor antigens Enhanced tumor targeting of cytotoxic payloads Masked cytokine targeting functional cytokine to tumor Fig. 1 | Sutro Biopharma’s deep R&D arsenal. The precise design drives adaptive and protective immunity. ADC, antibody–drug conjugate; iADC, immunostimulatory ADC; ISAC, immune-stimulating ADC. Brunilda Shtylla VP of Business Development Sutro Biopharma South San Francisco, CA, USA Tel: +1-650-801-6478 Email: [email protected] CONTACT B34 | March 2021 | www.nature.com/biopharmdeal
Transcript of Precision protein engineering to target oncology
A D V E R T I S E M E N T F E A T U R E
A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N T
Sutro Biopharmawww.sutrobio.com
Precision protein engineering to target oncologySutro Biopharma combines its powerful cell-free protein synthesis platform with clickchemistry to develop precisely engineered bioconjugate therapeutics for oncology.
Sutro Biopharma, a drug development and manu-facturing company headquartered in South SanFrancisco, is transforming biotherapeutics discoverywith a novel platform for cell-free protein synthesiscombined with site-specific conjugation to non-natural amino acids (nnAAs), which togetherallow for the precise design and rapid expressionof homogeneous therapeutic bioconjugates (Fig. 1).
XpressCF: the power of going cell-freeDesigning and producing complex proteins usingcell-based systems is expensive and time-consum-ing, often taking years from concept to clinic. Sutroreinvented this process using a cell-free platform,XpressCF, to produce discovery proteins consistentlyand quickly, allowing for the screening of thousandsof variants of a molecule to get to an optimized lead.
Core to XpressCF is Sutro’s proprietary cell-freeextract manufactured from a highly engineered bacte-rial cell line, which contains all the transcriptional andtranslational machinery needed to rapidly expressany desired protein from an encoding plasmid. Thesynthesis of proteins with XpressCF can be achievedovernight and does away with the need to make a newcell line for every new molecule, as required in tradi-tional cell-based expression systems. With proteinexpression reduced to a liquid-handling operation andthe ability to produce and screen thousands of pro-tein variants in parallel overnight reactions, the drugdiscovery process is greatly sped up and simplified.
Sutro’s complementary XpressCF+ platform fur-ther augments the cell-free process by incorporat-ing nnAAs at specific sites as a chemical handleto attach payloads selectively via highly efficientclick chemistry conjugation. This capability enabledSutro to create highly optimized clinical-stage anti-body–drug conjugates (ADCs), bispecific ADCs andearly-stage immunostimulatory ADCs. The processleaves natural amino acids unmodified—resulting ina homogeneous and well-controlled drug product.The combination of the two platform technologiesallows Sutro to screen many variants with differentpositioning of nnAAs in the protein sequence, permit-ting empirical identification of the optimal molecule.
“Sutro’s XpressCF technology uses a proprietarycellular extract, which is a key element that guar-antees robust protein manufacturing,” said TrevorHallam, CSO of Sutro. “That, in combination withour ability to make a single homogenous therapy,sets our technology apart—not only from a drugdevelopment standpoint, but also in our ability tosupply the therapy needed to power our clinicaltrials without cell-based limitations.”
The ability of Sutro’s platform to selectively conju-gate payloads precisely at specific sites in proteinsis key to overcoming a problem that besets other
approaches: heterogeneity in a single drug. Standardapproaches, in which payloads are conjugated to nat-ural amino acids, lack control over the exact locationof conjugation and how many payloads are addedto each protein, resulting in a drug product that is amixture of a number of different protein conjugates.
By contrast, for Sutro, the end result is a preciselyengineered, fully optimized and homogeneous drugproduct, which Sutro believes translates to a broadertherapeutic window and better patient outcomes.
“Sutro is working to address unmet needs bydeveloping targeted therapies that can evolve withever-changing cancer cells,” said Bill Newell, CEO ofSutro. “Our technology enables precision and speed.”
Amongst Sutro’s pipeline are four unique ADCs.STRO-002 is an ADC targeting folate receptor-αwith four cleavable hemiasterlin linker-warheads perantibody currently in phase 1/1b in advanced ovariancancers. STRO-002 has shown good patient toler-ability with no ocular toxicity and a potentially bettertherapeutic index than other ADCs in developmentfor ovarian and endometrial cancers. STRO-001, anADC targeting CD74 with two non-cleavable may-tansinoid linker-warheads, is currently in phase 1astudies for lymphomas and multiple myeloma. WhileSTRO-001 continues in dose escalation, it has shownsigns of an improved therapeutic index versus otherADCs in hematological cancers and also exhibits noocular toxicity. In collaboration with Bristol MyersSquibb, CC-99712, an ADC against B cell matura-tion antigen, is being studied in phase 1/1b trials formultiple myeloma, and, in a separate collaborationwith Merck KGaA, (operating as EMD Serono inthe US and Canada), M1231, a bispecific ADC thattargets MUC1 and EGFR, is in phase 1/1b trials for
non-small-cell lung cancer and esophageal cancer.Additional drug candidates enabled by Sutro’s
platform currently in development are cytokinederivatives, in collaboration with Merck & Co., anda 24-valent Pneumococcal conjugate vaccine beingdeveloped by its spinout, Vaxcyte, Inc.
Sutro has established the world’s only cell-free pro-tein production GMP facility in San Carlos, California,which can produce engineered proteins of consistentquality at scale and provide drug material throughclinical development. Recently, dry powder formula-tions of the cell-free extract have further optimizedthe manufacturing process, enabling large-scaleextract production with ease of shipping and flex-ibility of use for future product commercialization.
Moving forwardSutro seeks to expand its partnerships with pharma-ceutical companies, whose long-standing expertisein disease biology has synergistically combinedwith the power of Sutro’s differentiating biologicdesign, discovery and manufacturing technology.“Our ultimate goal is to leverage these powerfulcollaborations to create best-in-class therapeuticsand help fill the unmet needs of cancer patients withmore targeted therapies”, said Newell.
Conjugated antibody Cytokinederivative
Bispecific antibody
Cytokine
Releasablemask
Drugproperties
Structure
Optimized formatand anity;
improvedspecificity for
optimizedtherapeutic
window
ISAC:Immune-
stimulatingADC:
targetingnovel
payloads
Site-specificdual drug conjugatewith complementary
modalities(TME modulator
± immunemodulator)
Masked cytokinederivative
ADCor ISAC
Immune cell engager iADCModality BispecificADC
Tumoror stromal
antigen
Tumorantigen
Tumorselective
mask
Tumorantigen
Immunecell
engager
Target Dualtumor
antigens
Enhancedtumor
targeting ofcytotoxicpayloads
Maskedcytokinetargetingfunctionalcytokine to
tumor
Fig. 1 | Sutro Biopharma’s deep R&D arsenal. The precise design drives adaptive and protective immunity.ADC, antibody–drug conjugate; iADC, immunostimulatory ADC; ISAC, immune-stimulating ADC.
Brunilda ShtyllaVP of Business DevelopmentSutro BiopharmaSouth San Francisco, CA, USATel: +1-650-801-6478Email: [email protected]
CON
TACT
B34 | March 2021 | www.nature.com/biopharmdeal
