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

A D V E R T I S E M E N T F E A T U R E

Vincerx Pharma, Inc.vincerx.com

Vincerx—next-generation antibody–drugconjugates with enhanced therapeutic windowsVincerx applies a modular approach in the development of antibody–drug conjugates by incorporating novel targetingand safety features. The company’s lead compounds exhibit high efficacies with minimal toxicities that are expectedto improve therapeutic windows. Vincerx believes that partners with first-in-class antibodies, clinical stage antibodiesor ADCs against promising targets will benefit from Vincerx’s next-generation payload-linker technologies.

Vincerx Pharma is a clinical-stage biotechnologycompany, with aspirations to address the unmetmedical needs of cancer patients with paradigm-shifting therapies. The company’s antibody–drugconjugate (ADC) platform combines cutting edgeeffector chemistries, payloads, and linkers toenhance the efficacy and safety of ADCs. Thekey features of the Vincerx platform are:• a large toolbox of effector chemistries and

potent payload classes, including kinesinspindle protein (KSP) inhibitors, with a novelmode of action, to address a broad range ofcancer targets,

• tunable features that allow optimization of apayload’s physicochemical profile, e.g., intra-cellular trapping or bystander killing, to matchtarget tumor biology,

• novel linker chemistries for tumor specific payloadrelease by legumain, a protease with a uniquecleavage sequence overexpressed in cancers.

Vincerx’s pipeline includes a clinical-stage smallmolecule drug program in diffuse large B celllymphoma and other select cancers and a pre-clinical stage bioconjugation platform and next-generation antibody–drug conjugates to tacklesolid and liquid tumors.

“Vincerx is a young company poised to deliverparadigm-shifting therapeutics to address theunmet medical needs of cancer patients world-wide,” said Ahmed Hamdy, CEO and cofounderof Vincerx. “We are particularly focused on har-nessing our versatile toolbox of innovative link-ers, payloads and bioconjugation chemistries toadvance the next generation of small moleculeand antibody–drug conjugates with potential formaking significant inroads into the fight againstsome of the more intractable forms of cancer.”

Vincerx has an experienced management teamto advance the company’s therapeutic platform ofnext generation ADC technologies from discoveryto approval, including leveraging the synergies oflicensing or strategic partnerships. The company’sgoal is to rapidly identify candidate ADCs againstpromising targets or address challenges of clinical-stage antibodies whose development into ADCs hasbeen limited by current payload-linker chemistries.

Rekindling the magic bulletMore than a century ago, the German physician-scientist Paul Ehrlich introduced the concept of aZauberkugel (magic bullet) compound that selec-tively targets a disease-causing microorganismor cell without affecting other beneficial microor-ganisms or healthy cells. Initially, the Zauberkugelconcept drove the design of chemical compoundsexhibiting improved differential affinities for par-ticular pathogens or target cells. Eventually, thedaunting challenge of trying to improve targetspecificity and toxicity of a single molecule usingmedicinal chemistry led to the idea of decon-structing the Zauberkugel concept and develop-ing each of its parts separately to then combinethem into a new and improved hybrid Zauberkugel.

This is how ADCs were born, therapeutic agentscombining a targeting moiety, the antibody, witha cytotoxic moiety, the drug payload.

In the second half of the 20th century, ADCsrapidly progressed from rudimentary constructsof polyclonal antibodies noncovalently linkedto a cytotoxin, to mouse monoclonal antibod-ies (mAbs), and eventually humanized mAbs,covalently linked to a drug payload. Along the way,many lessons were learned regarding drug potency,antibody specificity, and stability of the linker bind-ing the drug to the mAb. All those efforts led to theUS Food and Drug Administration approving thefirst ADC, Mylotarg, for the treatment of acutemyeloid leukemia in 2000 and to a surge of ADCsin the pharma pipeline—a total of nine have beenapproved, five of them in the last two years.

“While the pharma pipeline of ADCs for oncologi-cal applications remains vibrant, the ADCs in theclinic have revealed a number of safety and efficacychallenges,” said Hamdy. “At Vincerx we have takena modular engineering approach to improve theperformance of key ADC components, such as con-jugation chemistry, linker stability and functionality,and drug payload design. This allows us to custom-ize ADC development using individually optimized

Legumain linker• Cleaved by a very specific

lysosomal asparaginylendopeptidase enhancingselectivity for cancer cells

• Legumain overexpressionin cancer is associatedwith poor prognosis

Antibody• Optimized for

tumor selectivityand internalization

• Improves potency

Kinesin spindle protein inhibitor(KSPi) payload• Enzyme inhibitor with high

potency in dividing cells• Low/no toxicity in non-dividing

cells e.g. no neurotox

Cell trapper• Inhibits cell membrane permeability,

traps KSPi to accumulate in tumorcells until the cell divides and dies

• Released KSPi–cell trapper cannotenter healthy cellsKSPi–cell trapper

Antibody Legumain-cleavable

linker

Fig. 1 | Vincerx’s next-generation, modular antibody–drug conjugates for cancer. Vincerx has developed acustomizable antibody–drug conjugate platform that allows for the modular combination of antibodiesoptimized for tumor selectivity and internalization, with (1) a legumain linker for improved cancer cell–specific cargo release, (2) a novel kinesin spindle protein inhibitor (KSPi) payload of high potency in dividingcells, and (3) a cell trapper moiety that reduces KSPi’s cell membrane permeability, ‘trapping’ it inside thetarget cancer cells. Target-specific combination of these individually optimized building blocks allows theprecise tuning of therapeutic windows.

“Vincerx is a youngcompany poised to

deliver paradigm-shiftingtherapeutics to address theunmet medical needs ofcancer patients worldwide

Ahmed Hamdy, CEO andcofounder, Vincerx

B28 | March 2021 | www.nature.com/biopharmdeal

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

A D V E R T I S E M E N T F E A T U R E

components and layering theminwaysthatmaximizeon-target effects and minimize off-target toxicities.”

Vincerx’s two lead ADCs in preclinical develop-ment for hematologic malignancies are VIP943and VIP924, targeting IL3RA and CXCR5, respec-tively. They both incorporate the company’s novellegumain linker and KSPi payload.

Vital linksFunctionally, the antibody component of an ADC,its targeting moiety, and the drug payload of anADC, its pharmacologically active moiety—arethe main building blocks of ADCs. Operationally,though, the linker binding the two functional moi-eties is arguably another critical component ofan ADC because it provides not only a physicalbackbone to the ADC but also plays a central rolein determining its therapeutic window. Ideally, aneffective linker is designed (1) to stably attach tothe antibody to preempt premature release of thedrug payload in systemic circulation, and (2) to pro-vide a target-specific trigger to efficiently releasethe drug payload at its intended destination.

Vincerx’s proprietary linker technology takesadvantage of a lysosomal protease called legumainthat is overexpressed in cancer cells and associ-ated with poor prognosis. Legumain has exquisitesequence specificity and cleaves at a positionallyconstrained asparagine sequence. The antibodywith the legumain linker enhances the tumorspecificity of Vincerx’s ADC. As a result, the acci-dental release of the drug payload into systemiccirculation and a non-tumor target is minimizedby focusing the payload targeting and release in ahighly specific manner (Fig. 1).

Safely capping it offFor most ADCs, the cytotoxic effect of the drugpayload is activated upon cleavage of the drugpayload from the antibody-linker portion of theADC. While the release of the drug payload hasbeen engineered to be target cell-specific in mostADCs, a certain proportion of non-specific cleav-age remains a safety liability for many ADCs. Oneway to circumvent this problem is by engineeringa prodrug principle into the payload (Fig. 2).

A prodrug technology is another differentiationin Vincerx’s bioconjugation toolbox to increasethe therapeutic window of ADCs. The prodrugprinciple is implemented with a legumain-cleav-able peptide cap on the KSP inhibitor payload.Activation of the prodrug occurs upon internal-ization and cleavage of the peptide cap by thelegumain present in tumor cell lysosomes.

Novel anti-mitotic bulletsThe efficacy of an ADC is highly dependent on thepotency of its drug payload. Most ADCs in devel-opment and on the market use one of two classesof very potent ADC drug payloads that bind anddisrupt microtubules or DNA. These cytotoxic pay-loads have been selected for their high potency inthe picomolar range to maximize cell killing but theyare also toxic to non-dividing or non-cancer cells.

The discovery of novel cytotoxic payloads iscomplex due to the need to minimize their hydro-phobicity to preempt ADC aggregation and theneed to generate chemistries amenable to stablelinker conjugation. Ultimately, the goal is to dis-cover novel payload classes based on alternativemechanisms of action that will result in ADCs withexpanded therapeutic windows.

Vincerx’s KSP inhibitor represents a new class ofADC payload with multiple technology enhance-ments. KSP is involved in the separation of cen-trosomes in the G2/M phase of the cell cycle.Inhibiting this critical step in the cell cycle has amarked antitumor effect, but healthy, non-dividingcells are not affected by it. The KSP inhibitor exhibitssub-nanomolar cytotoxic potency and is compat-ible with a variety of linker chemistries at differentattachment sites allowing for stable conjugationto antibodies. In hematologic malignancies, cancercells are juxtaposed against normal cells. In thiscontext, bystander activities associated with typi-cal ADCs are undesirable and may contribute todose-limiting toxicities. This issue is addressed bymodifying the payload with a hydrophilic moietycalled ‘cell trapper’. This modification enables intra-tumoral accumulation of the active payload andfurther blocks uptake into healthy cells once it isreleased into circulation, thus having a beneficialimpact on efficacy and safety. Finally, due to thehydrophilicity of the KSP inhibitor payload, highdrug to antibody ratios (DARs) can be achievedwithout any risks for aggregation, or associatedside effects. By contrast, the hydrophobicity ofmany existing drug payloads allows passive diffu-sion through the cell membranes. The company’stwo lead ADC programs use this novel KSP inhibitoras their drug payloads.

“ADC engineering has come a long way overthe past few decades, but at Vincerx we feel thatthe development of next-generation ADCs thatincorporate extra safety features in a modular wayand optimized for specific applications is going tobe the deciding factor in propelling the promise ofADCs to the next level,” said Hans-Georg Lerchen,CSO of Vincerx. “Our unique combination of celltrapper and legumain linker chemistries are a firstin the industry, and we are very excited about itspotential to significantly improve the therapeuticwindow of ADCs.”

Partnerships in ADC innovationBacked by a strong IP portfolio and an excel-lent R&D team, Vincerx is poised to deliver thenext generation of ADCs in short order over thenext two to three years. The company’s modularplatform offers many partnership possibilities todevelop innovative next-generation ADCs.

Vincerx’s pipeline of ADCs in preclinical devel-opment for a range of intractable forms of cancerexemplifies opportunities for discovery and devel-opment partnerships. The flexibility of the platformcould also help accelerate partner’s ADC develop-ment programs by incorporating select Vincerxinnovations into their ADC designs. As a result,Vincerx believes its platform will be attractive topartners with antibody technologies to addresspromising targets or clinically validated antibod-ies, which ran into limitations with conventionalpayload linker chemistries.

According to Hamdy,�“the full promise ofEhrlich’s Zauberkugel concept has long eluded us,but we feel that the innovation platform we havedeveloped at Vincerx will allow us, in collaborationwith our partners, to bring better and safer curesfor cancer patients around the world.”

Stuart Hwang, Chief Business OfficerVincerx Pharma, Inc.Palo Alto, CA, USATel: +1-650-666-0551Email: bizdev@vincerx.com

CON

TACT

Antibody Smallmolecule

IntracellularExtracellular

KSPi Cytotoxicagent

Off On

Targeting agent Linker Payload CELLTRAPPER

Therapeutic window

Targeted cell killing

By-stander effect

No by-stander e�ect — ADC exampleMaximize protection of healthy tissues

By-stander effect

By-stander e�ect — SMDC exampleMaximize killing of neighboring cells

Fig. 2 | Vincerx’s modular bioconjugation platform provides flexibility in targeting. Vincerx’s versatilebioconjugation platform allows for the precise tuning of the desired bystander effect of a therapeutic agent.The range of possibilities is illustrated by the design of highly tumor cell-specific antibody–drug conjugates(ADCs) with minimal bystander effect to small molecule-drug conjugates (SMDCs) that maximize killingof surrounding cells. KSPi, kinesin spindle protein inhibitor.

“Our unique combinationof cell trapper and

legumain linker chemistriesare a first in the industry, andwe are very excited about itspotential to significantlyimprove the therapeuticwindow of ADCs

Hans-Georg Lerchen,CSO, Vincerx

www.nature.com/biopharmdeal | March 2021 | B29