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268600, CP-BMP2, 골성형 촉진제, 셀리버리, 유전체조절, 일동제약, 코로나19 폐렴, 파킨슨병, 패혈증 치료, 희귀질환, 싸이토카인, 

(268600) 셀리버리 - (2) 영문판 번역본

 

  • 동사는 2014년 3월 14일에 설립되어, 약학 및 의학 연구개발업과 생물학적 제제 제조업을 주요사업으로 함.
  • 동사는 플랫폼 기술인 '약리물질 생체 내 전송기술'을 기반으로, 신약후보물질 및 연구용 시약을 연구개발함.
  • 주력제품인 후보물질 CP-BMP2(골형성 촉진제)는 운반체 및 이차적 외과 수술 없이 적용 가능한 세포/조직투과성 재조합단백질로 기존 치료제제인 rhBMP2에 비해 편의성이 획기적으로 개선됨.

 

 

OVERVIEW

사명

Cellivery는 셀러 버리의 독점적 치료 분자 분자 전달 시스템 (TSDT) 플랫폼을 기반으로 세포 / 조직 투과성을 가진 혁신적인 약물 후보 물질을 개발하는 생명 공학 회사입니다.

사업 모델

TSDT는 잠재적 치료 목표를 식별하고 검증하는 강력한 방법을 제공합니다. 따라서 Cellivery는 희귀 질환을 표적으로하기 위해 소분자, 항체 및 펩티드와 같은 TSDT 적용화물을 개발하고 있습니다.



Cellivery의 치료제 후보 물질은 암, 염증, 비만, 대사 질환 및 신경 퇴행성 질환을 포함한 생명을 위협하는 질병의 예방 및 치료를 위해 개발되고 있습니다.

경쟁력

Cellivery의 사명은이 독특하고 생명을 구하는 치료제를 상용화하여 치료하기 어려운 질병을 앓고있는 환자를 돕기 위해 우리 사회에 기여하는 것입니다.

시장

Cellivery의 전략은 전 세계 제약 및 서비스 회사와 협력하는 것입니다. 협력을 통해 Cellivery는 약물 후보를 강화 및 추가 개발하고 상업화 및 마케팅 프로세스를 촉진하여 환자를보다 빠르고 효과적으로 도울 수 있습니다.

Cellivery는 현재 글로벌 제약 회사와 협력하여 새로운 약물 후보를 발견하고 글로벌 CMO 및 CRO와 협력하고 있습니다.

 

GREETING

설립자 & CEO
조대웅

친애하는 선생님 / 부인 ..

Incorporated의 Cellivery Therapeutics (이하“회사”또는“이동”)를 소개하겠습니다. Cellivery의 사명은 생명 ​​공학 산업에서 단백질 기반의 약물 발견 회사가되어 독점적 인 TDT (Therapeuticmolecule Systemic Delivery Technology)를 통해 세포에 들어갈 수있는 치료제를 개발하는 것입니다. 다재다능한 관리 팀과 활발한 자문위원회 구성원은 기술 및 산업 경험을 통해 생명을 구하는 치료제를 상용화하고 생명 공학 및 제약 회사와 수익 창출 파트너십을 구축하는 회사의 사명을 수행하는 데 고유하게 적합합니다.

원형질막은 일반적으로 불 투과성 장벽으로 작용하여 단백질 및 기타 거대 분자가 세포로 유입되는 것을 방지합니다. 그러나 Cellivery의 독점적 인 TSDT는 기능적으로 활성 인 거대 분자가 빠르게 세포막을 통과 할 수 있도록합니다. 상기 방법은 펩티드, 전체 단백질, DNA 단편 및 약물과 같은 다른 생물 활성 물질로 조작 될 수있는 거대 분자 형질 도입 도메인 (MTD)으로 불리는 특수한 소수성 세포-침투 펩티드 (CPP)를 이용한다. 추가적인 세포 내 트래픽 신호를 이용하여, 형질 도입 된 거대 분자를 특정 세포 위치로 안내 할 수있어, 세포 내 단백질 기능에 영향을 미치는 효과적인 방법을 제공한다.

 

이전에, MTD에 융합 된 재조합 세포 투과성 (CP-) 단백질이 치료 활성화물 단백질을 살아있는 세포로 전달하기 위해 개발되었지만, 낮은 용해도 및 수율로 인해, 박테리아 시스템에서 발현 된 융합 단백질은 가용성 형태로 정제하기가 어려웠다. 단백질 기반 생체 치료제로서 CP- 단백질의 추가 임상 개발에 대한 중요한 약점을 해결하기 위해, 고급 MTD (aMTD)라고하는 소수성 CPP의 엄청나게 향상된 형태가 중요한 인자 기반 펩티드 분석을 통해 개발되었습니다. Cellivery에서 우리는 소설 aMTDs에 의해 가능 TSDT 암 및 기타 치명적인 질병에 대 한 소설 단백질 치료법을 제공 할 수 있음을 시연했다.

이 시장의 대부분의 회사와 마찬가지로 회사의 평가는 현재 수익이 아닌 지적 재산권, 지속적인 파트너십 및 파이프 라인의 가치를 기반으로합니다. 이 회사의 과학적 전문 지식과 핵심 역량을 통해 Cellivery는 세포 투과성 단백질 치료제의 개발 및 사용에 전념하는 세계 최고의 생명 공학 회사가 될 수 있습니다.

TSDT는 생물 의학 연구 분야에서 많은 응용 분야를 갖춘 플랫폼 기술입니다. 특히, TSDT는 잠재적 치료 목표를 식별 및 검증하고, 단백질 기반 약물을 살아있는 세포 및 동물에 전달하는 방법을 제공한다. 회사의 지적 재산 가치를 극대화하기 위해 회사는 특정 기술에 대한 라이센스를 부여합니다.

Cellivery는 또한 핵심 형질 도입 기술을 사용하여 기능성 단백질 상호 작용을 빠르게 식별하는 새로운 단백질 기반 약물 발견 플랫폼을 구축 할 것입니다. 이러한 플랫폼 개발 비용은 경우에 따라 장기적인 기업 연구 개발 제휴를 설정하여 표시 될 것입니다. 이러한 제휴는 회사의 단기적인 반복 수익을 창출 할 것입니다.

Cellivery의 치료제 후보 물질은 다양한 암을 포함한 생명을 위협하는 치명적인 질병을 예방하기 위해 개발되고 있습니다. 이 회사의 후속 약물 발견 프로그램은 증상이나 병인의 일시적인 억제가 비용 효과적이고 높은 삶의 질과 관련된 장기적인 이점을 생성하는 다른 질병에 중점을 둘 것입니다.

Cellivery의 장기적인 목표는 수익 창출 파트너십을 구축하고 강력한 지적 재산 및 의약품 포트폴리오를 구축하며 독점적 인 생물학적 정보를 만들어 주주의 가치를 계속 높이는 것입니다. 우리의 목표는 개발 단계 이후 또는 시장에 따라 3 년 이내에 초기 공모를하는 것입니다.

결론적으로, TSDT는 상당한 가능성을 가지고 있으며 Cellivery는 TSDT를 향상 및 확장하고 기술을 개념적에서 치료 적 현실로 옮길 수있을 것입니다.

저의 의견이 회사의 목표와 가치를 이해하는 데 도움이 되었기를 바랍니다.

진정으로,

조대웅 박사

설립자 및 CEO
Cellivery Therapeutics, Inc.
서울

 

 

Pipeline

CV-01

파이프 라인 | CV-01
TSDT 플랫폼

aMTD (Advanced Macromolecule Transduction Domain) 기반 치료 약물 분자 시스템 전달 기술 (TSDT)은 새로운 약물의 발견 및 개발을위한 강력한 플랫폼 기술인 치료 분자의 세포 투과성을 제공하는 소수성 세포-침투 펩티드 (CPP)로 가능합니다. 생체 내.

이전 세대의 소수성 CPP는 분비 된 단백질의 소수성 신호 펩티드로부터 유래되었으며, 동물에서 생물학적으로 활성 인 펩티드 및 단백질을 전달하는데 사용되었다. 그러나, 추가적인 임상 개발 및 적용을 위해 이전 세대의 소수성 CPP 서열을 사용하여 세포 투과성 치료 단백질을 개발하려는 많은 노력이 생리 학적 완충 조건에서 재조합 단백질의 불량한 용해도 및 비교적 낮은 세포 투과성으로 인해 방해를 받아왔다. Cellivery는 개선 된 소수성 CPP를 개발하기 위해 모든 1 세대 및 2 세대 소수성 CPP 서열의 서열을 분석하고, 원형질 막을 가로 지르는 효율적인 단백질 전위와 관련된 6 가지 '핵심 요소'를 식별했습니다. 6 개의 CF의 상이한 순열을 포함하고 진보 된 거대 분자 도입 도메인으로 지정된 136 개의 합성 펩티드가 개발되었다

이전 세대의 CPP와 비교하여, aMTD를 함유하는 단백질은 평균 13 ± 1.1 배 더 큰 세포-침투 능력을 나타냈다.

aMTD- 매개 치료 분자 흡수는 원형질막의 직접 침투를 포함한다. 특히, 흡수는 ATP, 세포 표면 단백질 또는 미세 소관 기능을 요구하지 않았다. 그러나, 칼슘 킬 레이터의 존재하에 흡수는 폐지되었고 또한 4 ° C에서 온도가 차단되었다.

마지막으로, MTD 가능 TSDT 플랫폼은 세포 대 세포 전달을 통해 치료 분자를 세포 및 조직으로 내재화 할 수있다.

그러나, 거대 분자는 결합 파트너와 높은 표적 특이성을 가지므로, 메커니즘 특이 적 표적 요법이 가능해진다. 일반적으로, 세포에 들어간 CP- 단백질은 소분자 약물과 유사한 방식으로 모든 곳에서 퍼집니다. 그러나, 소분자 약물과 달리, aMTD / SD- 융합 재조합 단백질은 CP- 단백질이 그의 표적과 특이 적으로 상호 작용하는 능력을 갖기 때문에 정확한 표적에 결합하지 않으면 기능하지 않는다. 이 경우, 친화도는 세포 분포에서 표적 수용체의 역할을한다. 또한 선호도는 선택성을 제어하고 특이성을 정의합니다. 궁극적으로, CP- 단백질은 강판 특이성으로 인해 소분자 약물보다 적은 표적 외 효과를 생성합니다.

aMTD 가능 TSDT 플랫폼은 여러 질병 영역에 걸쳐 많은 치료 분자에 적용될 수 있습니다. 입증 된 생물학적 활성을 갖는 치료 분자는 단순히 aMTD를 실험적으로 융합시킴으로써 세포 투과성 의약 후보로 쉽게 개발 될 수있다. aMTD에 의해 가능해진 TSDT는 단백질 기반 생물 치료제의 발견 / 개발을위한 플랫폼 기술로서 효율적이고 비용 효율적으로 사용될 수있다.

CV-02

PIPELINE | CV-02
iCP-SOCS3

사이토 카인 신호 전달 억제제 3 (SOCS3)은 JAK 키나제 활성을 억제하고 활성화 된 사이토 카인 수용체 복합체의 분해를 촉진하여 염증 억제로 인한 항 염증 및 항암 효과를 일으키는 JAK / STAT 신호의 음성 피드백 조절기로서 기능한다 -유도 사이토 카인 신호 전달. SOCS3의 상실은 일부 고형 종양의 성장 및 생존을 향상시킨다; 따라서, 단백질의 세포 내 수준을 보충하는 방법은 성장 또는 생존을위한 JAK / STAT 신호 전달에 의존하는 고형 종양에 대한 효과적인 요법을 제공 할 수있다.

JAK / STAT 신호를 음성으로 제어하기 위해, 우리는 이전에 차단 가능성을 탐색하기 위해 FGF4에서 유래 한 소수성 CPP (막 이동 모티프 : MTM)의 이전 세대에 의해 가능해진 세포 투과성 SOCS3 재조합 단백질 (CP-SOCS3)을 개발했다. 사이토 카인-유도 신호 전달 경로 (Nat Med. 2005; 11 : 892-898). 그러나, 이들 이전에 개발 된 재조합 CP-SOCS3 단백질은 극히 낮은 용해도, 수율 및 상대적으로 낮은 세포-및 조직-투과성을 나타냈다. 이러한 한계를 극복하기 위해, 본 발명자들은 신규 소수성 CPP, 고급 거대 분자 형질 도입 도메인 (aMTD)에 융합 된 재조합 SOCS3 단백질을 새롭게 개발하여 세포 투과성 (iCP)으로 명명 된 막 투과 능력의 용해도, 제조 수율 및 효율을 크게 증가시켰다. -SOCS3 단백질.

iCP-SOCS3는 단백질 기반 세포 내 대체 요법을 통해 간암, 췌장암, 폐암, 결장 직장암, 위암 및 교 모세포종 및 염증성 장애를 비롯한 다양한 암을 치료할 수있는 치료 적 적용 성을 갖는다.

iCP-SOCS3은 SOCS3의 이전에 기재된 효과와 일치하는 암 관련 표현형을 억제하고, 아 pop 토 시스를 유도하고, 바이오 마커 발현 (예를 들어, 세포주기, 아 pop 토 시스, 혈관 신생)의 변경을 촉발시켰다. 대조적으로, iCP-SOCS3는 비 암성 세포의 증식 및 아 pop 토 시스에 영향을 미치지 않았다. 또한, iCP-SOCS3는 또한 다양한 암 세포 유래 이종 이식편 (CDX) 모델에서 종양 성장을 유의하게 억제하고 생체 내에서 종양 혈관 신생을 유의하게 억제하여, 종양 혈관 신생의 억제를 초래 하였다. 또한, iCP-SOCS3은 STAT3 인산화를 억제하고 염증 유발 성 사이토 카인의 분비를 감소시켜 염증성 장 질환 (IBD)의 진행을 약화시키고 급성 간 손상을 일으킨다.

iCP-SOCS3은 암 관련 표현형을 억제하고, 아 pop 토 시스를 유도하고, 바이오 마커 발현 (예를 들어, 세포주기, 아 pop 토 시스, 혈관 신생)의 SOCS3의 효과와 일치하는 변화를 유발 하였다. 대조적으로, iCP-SOCS3는 비 암성 세포의 증식 및 아 pop 토 시스에 영향을 미치지 않았다. 또한, iCP-SOCS3는 또한 다양한 암 세포 유래 이종 이식편 (CDX) 모델에서 종양 성장을 유의하게 억제하고 생체 내에서 종양 혈관 신생을 유의하게 억제하여, 종양 혈관 신생의 억제를 초래 하였다. 또한, iCP-SOCS3은 STAT3 인산화를 억제하고 염증 유발 성 사이토 카인의 분비를 감소시켜 염증성 장 질환 (IBD)의 진행을 약화시키고 급성 간 손상을 일으킨다.

 

CV-06

PIPELINE | CV-06
iCP-Parkin

손상된 뉴런을위한 BBB- 교차 단백질 구세주

파킨슨 병 (PD)은 도파민 성 (DA) 뉴런의 손실을 특징으로하는 신경 퇴행성 질환으로, 운동 이완, 진전 및 자세 불안정과 같은 임상 증상을 유발합니다. PD의 병리학적인 특징은 α- 시누 클레인의 비정상 축적으로 도파민 뉴런에서 루이 소체의 형성을 초래한다. 이러한 눈에 띄는 임상 특징은 신경 사멸의 원인이되는 기전과 도파민 성 뉴런이 차별적으로 영향을받는 이유를 이해하려는 노력에 초점을 맞추 었습니다. 이러한 신경 생성 미세 환경에서, E3 유비퀴틴 리가 제로서 기능하는 파킨 단백질은 PD 병인의 복잡성에도 불구하고 세포 구성 요소의 독성 및 비정상 축적으로부터 죽어가는 뉴런을 구제하는 것으로 보인다.

iCP-Parkin as a superior disease-modifying anti-PD agent

우수한 질병 수정 항 -PD 제제 인 iCP-Parkin


개선 된 세포 투과성 파킨 (iCP-Parkin)은 동급 최강의 파킨슨 병 (PD) 약물 후보로, 혈액 뇌 장벽 (BBB)에 침투하여 손상된 도파민 성 (DA) 뉴런을 회복 할 수 있습니다. TSDT (Therapeuticmolecule Systemic Delivery Technology)가 적용된 세포 / 조직 투과성 파킨 재조합 단백질입니다. 내인성 파킨과 마찬가지로, iCP-Parkin은 미토 파지 및 미토콘드리아 생물 발생을 통해 기능 이상 미토콘드리아를 회복함으로써 세포 보호 작용을 할 수 있습니다. iCP-Parkin은 병리학 적 α-Synuclein의 축적을 감소시켜 PD 표현형을 억제 할 수 있습니다. 현재 L-Dopa와 같은 전형적인 PD 치료는 뇌에서 도파민의 손실을 보충하는 증상 완화 약물을 사용하여 환자의 비정상적인 운동 기능을 일시적으로 회복시킵니다. 증상이 완화 될 수는 있지만 해결되지는 않습니다.

따라서 iCP-Parkin은 PD에 의한 세포 스트레스에 대한 신경 보호 기능을 가지고있어 PD 생물 치료제에 대한 질병 수정 요법으로 큰 잠재력을 가지고 있습니다.

Severance Hospital and Cellivery에서 수행 된 AAV-α-Synuclein- 유도 PD 마우스 모델에서, iCP-Parkin의 치료로 행동 결핍이 회복되었고, SN에서 병리학 적 α-Synuclein의 축적이 회복되었으며 티로신 하이드 록 실라 제 (TH) 수준.

현재 일동 제약 (주)과 공동으로 다양한 글로벌 GRO 및 CMO에서 iCP-Parkin의 전임상 R & D를 수행하여 임상 개발 프로세스로보다 신속하게 전진하고 있으며, Cellivery는 한국 최초의 보조금 수혜자입니다. Parkinson 's Research (MJFF 프로그램 : No.14241. 2017. 07 ~ 2019. 03)의 Michael J. Fox Foundation (MJFF)을 지원하기 위해 iCP-Parkin 연구를 설립했습니다.

 

CV-07

PIPELINE | CV-07
CP-BMP2

캐리어 없음! 뼈 재생을위한 유일한 간단한 주입!

뼈는 생애에 걸쳐 지속적으로 조직을 리모델링하는 유일한 기관이며 성인의 생식에 대한 재생 잠재력을 유지하는 몇 안되는 기관 중 하나입니다. 뼈 조직의 심각한 손상은 재생 과정 동안 뼈 형태 형성 단백질 (BMP)을 포함하여 TGF-β 패밀리의 골 성장 인자의 국소 공급을 필요로한다. 주로 BMP2는 골격 발달과 뼈 형성에 중요한 역할을합니다. 재조합 인간 (rh) BMP2 단백질-기반 접근법에 의한 임상 시험은 중증 골절 (예를 들어, 장골 비 유니온, 경골 골절 임플란트) 및 척추 융합의 치유를 촉진시키기 위해 적용되었다. 그러나 rhBMP2를 사용하면 몇 가지 단점이 있습니다. 체내에 짧은 체류 시간 및 낮은 조직 통합으로 인해,? rhBMP2의 사용은 다회 또는 고용량의 치료로 비싸다. 또한, rhBMP2 단백질-기반 접근법은 약리학 적 용량에서 수많은 부작용 (예를 들어, 이소성 골 형성)을 가지며, 효과적인 전달 방법을 갖지 않기 때문에 때때로 외과 적 시술이 필요하다.

TSDT 적용 rhBMP2 인 세포 투과성 BMP2 (CP-BMP2)는 담체 / 비계 또는 수술 절차없이 국소 주사로 손상된 부위 근처의 주변 세포 및 조직으로 빠르게 전달되어 손상된 뼈 조직에 상주 할 수 있습니다. rhBMP2와 함께 존재하는 빠른 분해 및 제거율 문제를 해결하기 위해 더 오랜 기간 동안. CP-BMP2는 Smad 골 형성 신호를 유의하게 활성화시키고 ALP를 강하게 유도 하였다. 또한, CP-BMP2는 혈장에서 우수한 지속성 및 향상된 안정성을 나타냈다. 우리는 또한 CP-BMP가 murine calvaria 임계 크기 결함 및 말 뒷다리 결함 모델에서 뼈 재생 (8 배 더 높음)을 현저하게 촉진한다는 것을 발견했습니다.

TSDT를 이용한 바이오 테라피 치료법을 이용하여 CP-BMP2를 차세대 골 형성 제로 개발하여 비용 / 환자 친화적 인 방식으로 국소 뼈 치유력을 향상시킵니다.

 

CV-08

PIPELINE | CV-08
CP-ΔSOCS3

식욕을 조절하는 지방 세포 분비 호르몬 인 렙틴의 비정상적인 조절은 과도한 체지방을 축적하여 만성적으로 병적 비만을 유발합니다.

시상 하부 뉴런에서 발현 된 렙틴 수용체 (ObR)에 대한 결합에서, 렙틴은 JAK / STAT 신호 전달을 유발하고, 음식 섭취와 지방 축적 사이의 항상성 균형을 유지하기 위해 음성 피드백 조절제로서 사이토 카인 신호 전달 신호 (SOCS3)의 억제의 발현을 유도한다. 그러나, 비만의 과도한 렙틴은 내인성 SOCS3의 수준을 증가시켜 "렙틴 저항성"을 증진시키고 렙틴에 의한 식욕 조절을 불가능하게한다. 이러한 현상으로 인해 렙틴 기반 치료법은 중증 비만 환자를 효과적으로 치료하는 데 실패했지만 이전에는 매력적인 항 비만 전략으로 간주되었습니다.

이 프로젝트의 목표는 고급 거대 분자 도입 도메인 (aMTD)을 사용하여 경쟁력있는 단백질 기반 억제제를 제공하여 SOCS3 및 ObR의 결합을 방해하는 것이 었습니다. 세포 투과성 (CP) 절단 된 SOCS3 재조합 단백질 (CP-ΔSOCS3)은 렙틴 저항성을 극복하고, 렙틴-유도 된 항-친 화성 신호가 중증 비만의 치료를 위해 유지 될 수 있는지를 조사하기 위해 개발되었다.

본 발명자들은 CP-ΔSOCS3가 혈액 뇌 장벽 (BBB)을 투과함으로써 시상 하부를 포함하는 세포 및 조직으로 효율적으로 전달되고, 시험 관내 및 생체 내에서 ObR 및 강화 된 렙틴 신호 전달과 직접 상호 작용하는 것을 관찰 하였다.

CP-ΔSOCS3로 처리 된식이 유발 비만 (DIO) 마우스는 규칙적인 지방식이 (RFD) 조건 하에서 체중의 26 % 감소 및 고지방식이 (HFD) 조건 하에서 체중의 12 %가 식욕 조절 마커 및 에너지 소비 마커의 발현. 또한, CP-ΔSOCS3는 지방간을 개선하고 비만 마우스의 총 콜레스테롤 수준을 감소시켰다. 또한, CP-ΔSOCS3는 DIO 마우스에서 혈당 수준을 감소시켜 II 형 당뇨병에 대한 치료 효과를 나타낼 수 있음을 나타냈다. 따라서, 본 발명자들은 II 형 당뇨병뿐만 아니라 정상적인 식욕을 회복시키기위한 메카니즘-특이 적 항 비만 제로서 aMTD에 융합 된 CP-ΔSOCS3의 치료 적 적용 성을 성공적으로 입증 하였다.

현재 CP-ΔSOCS3는 전 세계 CRO 및 CMO에서 공정 개발, 제조, 캡슐화 및 분석 방법 개발을 수행하여 전임상 연구 중입니다.

 

CV-09

PIPELINE | CV-09
iCP-Cre

유전자 조작 마우스 모델은 생체 내 유전자 기능을 연구하는 데 유용한 도구입니다. 박테리오파지 P1에서 Cre 재조합 효소를 발견하여 포유류 세포에서 DNA 서열 특이 적 재조합을 유도함으로써 마우스 모델이 크게 발전했습니다.

Cre 재조합을 포함하는 적용은 조건부 돌연변이 유발, 마우스에서의 유전자 대체 및 염색체 공학, 및 조건부 유전자 발현을 포함 하였다. 그러나, Cre- 매개 유전자 조작 마우스 모델을 생성하는 과정은 비용이 많이 들고 시간이 많이 걸린다. 또한, 유전자 연구에서 부위-특이 적 재조합의 사용은 종종 특정 유형의 세포 및 원하는 발달 단계에서 재조합 효소 효소를 발현하는 어려움으로 인해 방해를 받는다. 더욱이, 조직-특이 적 Cre 발현에 의해 유도 된 조건부 돌연변이 체는 조직 발달을 방해 할 수 있고, 따라서 말기 분화 된 세포에서의 이후 연구를 배제 할 수있다.

이러한 한계를 극복하기 위해, 불 침투성 세포막을 가로 질러 세포 투과 펩티드 (CPP)를 가진 단백질의 세포로의 단백질의 전달은 유전자 기능을 정의하기 위해 유전자 조작 된 마우스 모델을 다루는 매력적인 전략으로 제안되어왔다. 직접 도입 된 세포 투과성 재조합 단백질은 Cre 마우스 또는 바이러스 전달과 같은 다른 방법보다 훨씬 쉽고 빠르며 비용이 적게 듭니다.

이를 위해, 본 발명자들은 신규 한 소수성 CPP, aMTD에 융합 된 개선 된 세포 투과성 (CP) Cre 재조합 단백질을 새로 개발하여 막 침투 능력의 용해도, 수율 및 효율을 크게 증가시켰다. iCP-Cre 재조합 단백질은 다양한 배양 세포에서 높은 수준의 재조합을 유도했으며, 정맥 주사 후 다양한 유전자 조작 마우스 (ROSA26-LSL-LacZ, ROSA26-LSL-EYFP, ROSA26nT-nG, SOCS3f / f 등)에서 검사 된 모든 조직 (IV) 생체 내 전신 또는 기관-특이 적 (뇌, 간, 신장 등) 재조합을위한 국소 투여.

동물에서 게놈 공학을 위해 세포 투과성 Cre 재조합 효소를 사용한 단백질 형질 도입의 사용은 마우스 모델에서 유전자 기능을 정의하기위한 빠르고 효율적인 도구를 제공합니다.

CV-10,11

PIPELINE | CV-10,11
iCP-RFs/Cas9

말기 분화 된 체세포는 자기 재생을 촉진하고 만능 세포를 세포 분화로 이끄는 리 프로그래밍 인자 (RF)의 강제 발현에 의해 유도 만능 줄기 세포 (iPSC)가되도록 재 프로그래밍 될 수있다. RF는 2 가지 유형의 단백질을 함유하는데, 하나는 다 능성 상태 (OCT4, SOX2 및 NANOG)로 배아 줄기 (ES) 세포를 유지하기위한 것이고, 다른 하나는 자기 재생을 촉진하고 세포 분화 (CMYC, KLF4 및 LIN28)를 촉진하기위한 것이다.

이러한 발견에 기초하여, 배아 유래 줄기 세포의 사용과 관련된 윤리적 및 이식 거부 문제없이 환자 유래 iPSC로부터의자가 줄기 세포를 사용함으로써 치료 적 접근법이 개발되었다. 실제로, 인간 재생 의학에 iPSC를 적용하려면 RF를 체세포로 도입하기 위해 유전자 전이가 필요할 수 있습니다. 불행하게도, 유전자 전달을 통한 체세포 재 프로그래밍은 비교적 비효율적이며 DNA- 기반 발현 벡터의 게놈 통합으로 인해 잠재적으로 돌연변이 유발 적이다. 합성 변형 된 RNA 및 화학적 화합물에 의한 후성 유전 적 조절과 같은 DNA- 기반 발현 벡터와 관련이없는 다른 접근법은 실제 적용과는 거리가 멀다.

이러한 한계를 극복하기 위해, 본 발명자들은 신규 한 소수성 CPP, 진보 된 거대 분자 형질 도입 도메인 (aMTD) 및 가용화 도메인 (SD)에 융합 된 개선 된 세포 투과성 RF 재조합 단백질 (iCP-RF)을 새롭게 발명 하였다.

iCP-RF는자가 재생 능력의 확장 및 줄기 세포 특이 적 마커의 발현 (OCT4, NANOG, TRA-1-60, TRA)으로 고효율 (0.01 % ~ 0.1 %) 및 초기 콜로니 형성으로 줄기 세포 유사 콜로니를 유도합니다. -1-81). 또한, 3 개의 배엽 층의 안정적으로 분화 된 기형 종으로부터 iCP-RF에 의해 생성 된 줄기 세포-유사 콜로니를 확인함으로써, iCP-RF는 완전한 만능 특성을 갖는 줄기 세포를 유도하는 것으로 나타났다.

한편, 게놈 공학은 특정 유전자 서열을 인식하기 위해 유전자 편집 또는 복구를위한 기술입니다. 이 유전체 공학 기술은 식품, 의료 및 연구 시약과 같은 다양한 분야에 적용 할 수 있습니다. 특히 게놈 편집 기술은 유전자 모델의 치료에 적용 할 치료 모델에 사용됩니다.

CRISPR / Cas9의 최신 기술은 질병을 일으키는 DNA 돌연변이를 복구하기위한 게놈 편집을위한 강력한 도구입니다. 그러나 안전하고 효율적인 DNA 전달 시스템은 유전자 편집의 성공을 보장하는 데 중요합니다. TSDT를 사용한 세포 투과성 (CP) Cas9는 높은 세포 투과성을 가진 유전자 편집으로 간단한 처리를 가능하게합니다. DNA 전달없이 세포로 전달 될 수있게 해주는 혁신적인 시약입니다. CP-Cas9는 이전에 사용 된 플라스미드 및 mRNA 시스템과 비교하여 세포 내 형질 도입에 의해 유발되는 유전자 편집 효율이 증가된다. CP-Cas9의 이러한 장점은 유전자 연구뿐만 아니라 유전자 변형에도 적용될 수 있습니다. CP-Cas9는 또한 유전자 장애 환자에게 유도 만능 줄기 세포 (iPSC)를 사용하는 줄기 세포 치료에 적용될 수 있습니다.

Cas9 기술은 최근 특정 유전 질환을 가진 개인의 환자 유래 iPSC의 생산 및 특성화를 통해 질병 중심 연구에 적용되었습니다. 유도 된 iPSC의 발명은 특히 질병-유래 된 인간 iPSC의 생성과 관련하여 번역 연구를 크게 발전시켰다. 우리는 CP-Cas9가 유전자 변형 동물 모델, 심지어 줄기 ​​세포 연구 및 치료에서도 엄청난 변화를 가져올 것이라고 믿습니다. Cellivery는 CP-Cas9로 연구 또는 개발을 시작하려는 기관에 대한 아웃 라이센싱 기회를 제공합니다.

 

CV-14

PIPELINE | CV-14 

운동 실조증은 근육 운동의 자발적인 조정 장애로 정의 된 신경 퇴행성 질환입니다. 운동 실조증은 주로 운동의 조정을 담당하는 뇌의 일부인 소뇌 병변의 손상에 기인합니다. 운동 실조증의 증상은 심각하며 종종 약점을 유발합니다. 유전자 돌연변이와 관련된 운동 실조증의 일부 유형은 조기 사망으로 이어질 수 있습니다. 운동 실조증 치료에는 증상을 줄이고 삶의 질을 향상시키기위한 약물의 조합이 포함되지만, 이러한 요법은 신경 손실과 관련된 실질적인 임상 적 개선을 나타내지 않았습니다.

CV-14 프로젝트는 진행성 신경 발생 장애 및 심근 병증을 유발하는 단발성 상 염색체 열성 질환을 특징으로하는 특수 운동 실조증을 다루고 있으며 조기 사망으로 이어집니다. CV-14 단백질은 철 대사에서, 특히 미토콘드리아에서 철-황 클러스터 (ISC) 생합성 및 헴 생합성에서 중요한 역할을하는 것으로 알려져있다. CV-14 단백질의 결핍은 뉴런 및 심장 근육에서 철-황 클러스터 생합성 기능 장애, 미토콘드리아 철 과부하 및 산화 스트레스를 초래한다. 불 침투성 세포막을 가로 질러 단백질을 세포 내로 전달하는 단백질 대체 요법은 유전자 질환을 다루는 매력적인 전략으로 제안되어왔다. 이러한 이유로, 치료 분자 분자 시스템 전달 기술 (TSDT) 적용 세포 투과성 CV-14 단백질은 운동 실조증으로부터 보호하기 위해 손상된 뉴런 및 심근 세포로 체계적으로 전달되도록 개발되었다.

CV-14 프로젝트는 신경 기능을 강화시키는 효과적인 치료법으로 운동 실조로 고통받는 환자에게 크게 도움이 될 것입니다.

 

CV-15

PIPELINE | CV-15
iCP-NI

패혈증은 전 세계적으로 사망을 초래하는 5 대 질병 중 하나이며, 전신성 염증 반응으로 인해 임상 증후군으로 널리 알려져 있습니다.

패혈증은 미생물 감염, 심각한 부상 또는 외과 적 스트레스로 인해 '사이토 카인 폭풍 (cytokine storm)'이라는 염증 유발 성 사이토 카인의 과도한 분비로 발생합니다. 패혈증의 전 세계 발병률은 3 천만이며 전체 사망률은 20 % 이상입니다. 이는 매년 패혈증으로 인한 6 백만의 사망이 있음을 의미합니다. 또한, 패혈증 치료는 현재의 항균 요법 및지지 수단에 의해 적절하게 제어되지 않으므로 새로운 보조 치료가 필요하다.

이전에, 내 독소 혈증에 의해 유발 된 다양한 전 염증 경로를 억제하는 폴리펩티드는 섬유 모세포 성장 인자 4 (FGF4)의 신호 펩티드로부터 유래 된 막 전좌 서열 (MTS)로 지칭되는 1 세대 소수성 세포-침투 펩티드 (CPP)를 합성함으로써 개발되었다. NF-κB- 유래 핵 국소화 서열 (NLS)과 함께.

세포 투과성 핵 수입 억제제 (CP-NI)는 TNF-α, IL-6 및 IFN-γ와 같은 전 염증성 사이토 카인의 발현을 억제함으로써 심각한 급성 염증성 동물의 생존율을 증가시켰다. 그러나 CP-NI는 용해도가 낮기 때문에 주로 제조가 어려워 임상 적용 가능성이 낮습니다. 이러한 한계를 해결하기 위해, 향상된 세포 투과성 핵 수입 억제제 (iCP-NI)는 진보 된 거대 분자 도입 도메인 (aMTD)을 채택함으로써 개발되었으며 패혈증 동물 모델에서 우수한 안정성 및 활성을 입증 하였다. iCP-NI는 염증 유발 경로의 활성화를 성공적으로 억제하고 염증 유발 사이토 카인의 분비를 억제합니다. 또한, iCP-NI는 장기 부전을 보호함으로써 급성 중증 패혈증 마우스 모델에서 생존 성을 획기적으로 증가시켰다. iCP-NI의 강력한 치료 적 적용 성을 입증하기 위해 추가적인 임상 동물 모델과 안전성 연구를 통한 효능 연구가 진행 중입니다.

결과적으로,이 강화 된 치료제 인 iCP-NI는 패 혈성 쇼크와 같은 심각한 치명적인 염증성 증후군에 대한 독특하고 독창적 인 수단으로 개발 될 수 있습니다.

 

CV-16

PIPELINE | CV-16

단일 쇄 가변 단편 (scFv)은 가변 중쇄 및 가변 경쇄가가요 성 펩티드 링커에 의해 함께 연결된 항체의 가장 작은 기능성 항원-결합 도메인으로 구성된다.

scFv는 모 항체의 결합 특이성을 유지하고 모노클로 날 항체에 비해 몇 가지 장점을 제공합니다. scFv는 더 나은 조직 침투, 신속한 혈액 제거 및 낮은 면역원 성과 같은 개선 된 약동학 적 특성을 나타내어 더 나은 치료제를 만듭니다.

scFv는 항체와 비교하여 더 높은 조직 침투성을 갖지만,보다 높은 효능을 위해서는 전달 기술이 여전히 필요하다. scFv를 표적화 영역에 전달하는 것은 치료 후보로서 scFv를 개발하는 주요 장애물 중 하나이다. scFv를 세포 내에서 국 재화하기 위해, 많은 연구 조직이 나노 입자, 아데노-관련 바이러스 (AAV) 및 세포-침투 펩티드와 같은 다양한 전달 기술을 시도 하였다. Cellivery는 자사 기술인 치료 분자 시스템 전달 기술 (TSDT)을 scFv에 적용하고 Cell-Permeable CV-16을 개발했습니다.

scFv의 다양한 장점에도 불구하고, 적절한 전달 수단이 없기 때문에 치료제가되는 데 어려움이 있습니다 .CV-16은 표적 세포에서 scFv를 세포 내에서 국소화하여 효율성을 극대화하는 효율적이고 효과적인 전달 시스템을 제공합니다. scFv의 응용을 확대하여 궁극적으로 도움이 필요한 환자를 도울 것입니다.

CV-17

PIPELINE | CV-17

안티센스 올리고 뉴클레오티드 (ASO)는 표적화 된 유전자의 단백질로의 번역을 방지하기 위해 상보 적 메신저 RNA (mRNA)와 상호 작용하는 짧은 단일 가닥 올리고 데 옥시 뉴클레오티드이다.

따라서, 상보 적 서열과 안티센스 올리고 뉴클레오티드를 합성하는 것은 RNA에 결합함으로써 작용하는 것을 나타내는 약물 일 수있다. ASO는 임의의 RNA 서열을 설계하여 여러 가지 독특한 메커니즘을 통해 단백질 발현을 감소, 복원 또는 변형시킬 수 있으므로 광범위한 질병의 치료에 적용 할 수 있습니다.

ASO의 세포 내 전달은 표적 세포 내에서 효과적인 ASO 활성에 대한 주요 장벽으로 인식된다.

따라서, 불량한 세포 흡수 과정을 개선하기 위해, Cellivery는 자사 기술인 TSDT (Therapeuticmolecule Systemic Delivery Technology)를 사용하여 ASO의 세포 / 조직 투과성을 향상시켰다. CP-17은 질병 관련 유전자의 발현을 조절하는 새롭고 유효한 접근법을 나타낼 수 있으며 다양한 질병으로 고통받는 환자에게 크게 도움이 될 것입니다.

 

R&D

OVERVIEW

Research
&
Development

PROPRIETARY
TECHNOLOGY

원형질막은 불 투과성 장벽으로 작용하여 세포 내외부의 단백질 및 기타 거대 분자의 흐름을 제어합니다.

그러나 Cellivery의 독점적 인 치료 분자 시스템 전달 기술 (TSDT)은 기능적으로 활성 인 거대 분자가 빠르게 세포막을 가로 지르도록합니다. 상기 공정은 펩티드, 전체 단백질, DNA 단편 및 약물과 같은 다른 생물 활성 물질로 조작 될 수있는 특수한 세포 투과 펩티드 (CPP)를 이용한다. 추가적인 세포 내 트래 피킹 신호를 이용하여, 형질 도입 된 거대 분자를 특정 세포 위치로 안내하여 세포 내 단백질 기능에 영향을 미치는 효과적인 방법을 제공 할 수있다.

실제로 TSDT 플랫폼은 회사 외부의 개인이 다양한 응용 분야에서 잠재적으로 사용할 수 있다는 큰 관심과 논평을 불러 일으켰습니다. 생명 공학 산업 전반의 많은 활동에서 Cellivery의 TSDT 플랫폼에 대한 라이센스가 필요할 것으로 예상됩니다.

조대웅 박사와 그의 동료들이 발표 한 일련의 논문은 생물학적 활성 단백질을 포유류 세포와 조직에 전달하는 TSDT라는 과정을 설명했습니다. 이 기술은 살아있는 세포의 생화학 적 과정을 정량적으로 그리고 비정규 조건에서 제어 할 수있는 방법을 제공합니다. 이는 차세대 단백질 기반 치료제의 개발 단계를 설정합니다.

단백질은 세포 생화학 적 경로와 관련하여 특이 적으로 기능하기 때문에, 단백질 기반 요법은 통상적 인 소분자 기반 약물보다 부작용이 적을 것으로 예상된다. TSDT는 펩티드 및 단백질의 포유 동물 세포로의 흡수를 촉진시키기 위해 거대 분자 형질 도입 도메인 (MTD)으로 불리는 소수성 서열의 능력을 이용한다. 결과적으로, MTD- 융합 재조합 단백질은 "세포 투과성 (CP)"이라고한다.

TSDT는 다른 단백질 변환 기술보다 우수한 것으로 입증되었습니다. 특히, 유동 상 및 흡착성 세포 내 이입을 통해 단방향 단백질 흡수를 촉진하는 HIV Tat 및 다른 기본 서열의 사용. 이것은 세포 내 소포에서 대부분의 단백질을 격리 시키며, 이는 세포 내부의 단백질 카고를 포획하여 세포질 전달을 제한하여 생체 이용률을 낮춘다.

마지막으로, MTD 서열로 변형 된 단백질은 MTD 서열이없는 동일한 단백질과 비교하여 상당히 연장 된 제거 시간을 가졌다.

셀리버리 현재주가

셀리버리 뉴스내용

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268600, ASOS, Cell-Penetrating Peptides, cellivery, CPPs, MTD, MTDs, TSDT, tyrosine hydroxylase, 셀리버리

 

OVERVIEW

MISSION

Cellivery is a biotech company developing innovativedrug candidates with cell-/tissue-permeability based onCellivery’s proprietary Therapeuticmolecule Systemic DeliveryTechnology (TSDT) Platform.

BUSINESSMODEL

TSDT provides a powerful method to identify and validate potentialtherapeutic targets. Thus, Cellivery is developing TSDT applied cargossuch as small molecules, antibody, and peptides to target rare diseases.

 

Cellivery’s therapeutic drug candidates are being developedfor the prevention and treatment of life-threatening diseases,including cancer, inflammation, obesity, metabolic diseases, andneurodegenerative diseases.

COMPETITIVENESS

The mission of Cellivery is to commercialize this unique and life-saving therapeutics to contribute to our society in aiding patientswith hard-to-cure diseases.

MARKETS

Cellivery’s strategy is to collaborate with pharmaceutical andservice companies globally. By collaborating, Cellivery can strengthenand further develop drug candidates and expedite the process ofcommercialization and marketing in order to help patients quicklyand more effectively.

Cellivery is currently collaborating with global pharmaceuticalcompanies to discover new drug candidates and working with globalCMOs and CROs.

 

GREETING

Founder&CEO
Daewoong Jo,Ph.D.

Dear Sir/Madam,..

Please allow me to introduce Cellivery Therapeutics, Incorporated (referred to as the “Company” or “Cellivery” henceforth). The mission of Cellivery is to become a leading protein-based drug discovery company within the biotechnology industry, developing therapeutics capable of entering cells through proprietary Therapeuticmolecule Systemic Delivery Technology (TSDT). A well-rounded management team and active advisory board members are uniquely suited, through technical and industry experiences, to fulfill the Company’s mission to commercialize life-saving therapeutics and cultivate revenue-generating partnerships with companies in biotechnology and pharmaceuticals.

The plasma membrane normally acts as an impermeable barrier, preventing proteins and other macromolecules from entering cells. However, Cellivery’s proprietary TSDT allows functionally active macromolecules to rapidly traverse cellular membranes. The process utilizes specialized hydrophobic cell-penetrating peptides (CPPs), termed Macromolecule Transduction Domains (MTDs) that can be engineered into peptides, whole proteins, DNA fragments, and other bioactive substances such as drugs. With additional subcellular trafficking signals, transduced macromolecules can be guided to specific cellular locations, providing an effective way to influence intracellular protein function.

Previously, recombinant cell-permeable (CP-) proteins fused to MTDs to deliver therapeutically active cargo proteins into live cells were developed, but due to their low solubility and yield, the fusion proteins expressed in bacterial system were difficult to purify in soluble form. To address the crucial weakness for further clinical development of the CP-Proteins as protein-based biotherapeutics, tremendously enhanced form of the hydrophobic CPP, named advanced MTD (aMTD), was developed through critical factor-based peptide analysis. In Cellivery, we have demonstrated that TSDT enabled by the novel aMTDs could provide novel protein therapies against cancer and other lethal diseases.

The valuation of the company, as with most companies in this market, will be based on the value of its intellectual property, ongoing partnerships, and pipelines, rather than on current revenues. The scientific expertise and core competencies of the company will allow Cellivery to become the world’s foremost biotechnology company devoted to the creation and use of cell-permeable protein therapeutics.

TSDT is a platform technology with many applications in biomedical research fields. In particular, TSDT provides a method to identify and validate potential therapeutic targets, and to deliver protein-based drugs into live cells and animals. To maximize the value of the company’s intellectual property, the company will out-license specific technologies.

Cellivery will also use its core transduction technology to build novel protein-based drug discovery platforms that rapidly identify functional protein interactions. These platform developmental expenses will be defrayed, in some cases, by establishing long-term corporate research and development alliances. Such alliances will generate near-term recurring revenue for the company.

Cellivery’s therapeutic drug candidates are being developed for the prevention of life-threatening lethal diseases, including various cancer. The company’s subsequent drug discovery programs will focus on other diseases, in which the transient suppression of either symptoms or etiology would produce long-term benefits, that are both cost-effective and associated with a high quality of life.

Cellivery's long-term goal is to continue to increase the value of shareholders by building revenue-generating partnerships, establishing a strong intellectual properties and drug portfolios, and creating proprietary biological information. Our goal is to have an initial public offering after the development phase or within 3 years, depending on markets.

In conclusion, I believe TSDT has considerable promise and Cellivery will be able to enhance and extend TSDT and move the technology from conceptual to therapeutic reality.

I hope my comments have been useful to you in understanding the company’s goals and values.

Sincerely,

Daewoong Jo, Ph.D.

Founder & CEO
Cellivery Therapeutics, Inc.
Seoul, Republic of Korea

 

 

Pipeline

CV-01

PIPELINE | CV-01
TSDT Platform

Advanced Macromolecule Transduction Domain (aMTD)-enabled Therapeuticmolecule Systemic Delivery Technology (TSDT), a powerful platform technology for the discovery and development of the new medicinal drug, is enabled with hydrophobic cell-penetrating peptides (CPPs) that provide cell-permeability of therapeuticmolecules in-vivo.

Previous generations of hydrophobic CPPs were derived from the hydrophobic signal peptides of secreted proteins and used to deliver biologically active peptides and proteins systemically in animals. However, many efforts to develop cell-permeable therapeutic proteins by using previous generations of hydrophobic CPP sequences for further clinical development and applications have been hampered by poor solubility of the recombinant proteins in physiological buffer condition and relatively low cell-permeability. To develop improved hydrophobic CPPs, Cellivery analyzed sequences from all 1st and 2nd generation hydrophobic CPP sequences and identified 6 ‘critical factors’ associated with efficient protein translocation across the plasma membrane. 136 synthetic peptides were developed that incorporated different permutations of the 6 CFs and have been designated advanced macromolecule transduction domains

Compared to the previous generations of CPPs, proteins containing aMTDs displayedan average of 13±1.1-folds greater cell-penetrating ability.

aMTD-mediated therapeuticmolecule uptake involves direct penetration of the plasma membrane. In particular, uptake did not require ATP, cell surface proteins or microtubule function. The uptake, however, was abolished in the presence of calcium chelator and also blocked in temperature at 4°Csuggesting the requirements of aMTD-mediated uptake aremembrane integrity and fluidity.

Finally, aMTD-enabled TSDT platform is able to internalize the therapeutic moleculeinto cellsand tissues systemically via cell-to-cell delivery.

However, because macromoleculeshave high target specificity with the binding partner, it makes mechanism specific-targeted therapy possible. In general, having entered the cell, CP-Proteins spread everywhere in a similar way as small molecule drugs. However, unlike small molecule drugs, aMTD/SD-fused recombinant protein does not function without binding to its correct target because CP-Proteins possess the ability of interact with its targets specifically. In this case, affinity plays a role of target receptor in the distribution of cells. Moreover, affinity controls the selectivity and defines the specificity. Ultimately, CP-Proteins will produce fewer off-target effects than small molecule drugs by virtue of their grater specificity.

aMTD-enabled TSDT platform can be applied to many moieties of therapeuticmolecules across different disease areas. Therapeutic moleculeswith proven biological activities can easily be developed into cell-permeable medicinal candidate by simplyfusing aMTD empirically. TSDT enabled by aMTD can efficiently and cost-effectively be used as platform technology for discovery/development of protein-based biotherapeutics.

 

CV-02

PIPELINE | CV-02
iCP-SOCS3

Suppressor of cytokine signaling 3 (SOCS3) functions as a negative-feedback regulator of JAK/STAT signaling that suppresses JAK kinase activity and promotes degradation of the activated cytokine receptor complex resulting in the anti-inflammatory and anti-cancer effect due to suppression of inflammation-inducing cytokine signaling. Loss of SOCS3 enhances the growth and survival of some solid tumors; therefore, methods to replenish intracellular levels of the protein may provide an effective therapy against solid tumors dependent on JAK/STAT signaling for growth or survival.

To control the JAK/STAT signaling negatively, we previously developed cell-permeable SOCS3 recombinant protein (CP-SOCS3) enabled by a previous generation of hydrophobic CPP (membrane-translocating motif: MTM) derived from FGF4 in order to explore the possibility of blocking cytokine-induced signaling pathway (Nat Med. 2005;11:892-898). However, these previously developed recombinant CP-SOCS3 proteins showed extremely low solubility, yield, and relative low cell- and tissue-permeability. To overcome these limitations, we have newly developed recombinant SOCS3 proteins fused to novel hydrophobic CPP, advanced macromolecule transduction domain (aMTD), to greatly increase their solubility, manufacturing yield, and efficiency of membrane penetrating ability named as improved cell-permeable (iCP)-SOCS3 proteins.

iCP-SOCS3 has the therapeutic applicability to treat various cancers includinghepatoma, pancreatic cancer, lung cancer, colorectal cancer, gastric cancer and glioblastoma,and inflammatory disorders through protein-based intracellular replacement therapy.

iCP-SOCS3 suppressed cancer-associated phenotypes, induced apoptosis and triggered alteration in biomarker expression (e.g., cell cycle, apoptosis, angiogenesis) consistent withpreviously described effects of SOCS3. In contrast, iCP-SOCS3 did not affect proliferation and apoptosis of non-cancerous cells. In addition, iCP-SOCS3 also significantly suppressed the tumor growth in various cancer cell-derived xenograft (CDX) models and significantly inhibited tumor angiogenesis in vivo, leading to inhibition of tumor angiogenesis. Furthermore, iCP-SOCS3 inhibited STAT3 phosphorylation and reduced secretion of proinflammatory cytokines leading to attenuated progression of inflammatory bowel disease (IBD) and acute liver injury.

iCP-SOCS3 suppressed cancer-associated phenotypes, induced apoptosis and triggered alteration in biomarker expression (e.g., cell cycle, apoptosis, angiogenesis) consistent with previously described effects of SOCS3. In contrast, iCP-SOCS3 did not affect proliferation and apoptosis of non-cancerous cells. In addition, iCP-SOCS3 also significantly suppressed the tumor growth in various cancer cell-derived xenograft (CDX) models and significantly inhibited tumor angiogenesis in vivo, leading to inhibition of tumor angiogenesis. Furthermore, iCP-SOCS3 inhibited STAT3 phosphorylation and reduced secretion of proinflammatory cytokines leading to attenuated progression of inflammatory bowel disease (IBD) and acute liver injury.

 

CV-06

PIPELINE | CV-06
iCP-Parkin

A BBB-Crossing Protein Savior For Damaged Neurons

Parkinson’s disease (PD) isa neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons, leading to clinical symptoms such as exercise relaxation, tremor, and postural instability. The pathological hallmark of PD is the abnormal accumulation of α-synuclein, resulting in the formation of Lewy body in the dopaminergic neurons. These striking clinical features have focused efforts to understand the mechanisms responsible for neuronal death and reasons why dopaminergic neurons are differentially affected. In these neurogenerative microenvironment, Parkin protein, which functions as an E3 ubiquitin ligase, appears to rescue dying neurons from toxic and abnormal accumulations of cellular components despite the complexity of PD etiology.

iCP-Parkin as a superior disease-modifying anti-PD agent

An improved cell-permeable Parkin (iCP-Parkin) is our first-in-class Parkinson’s Disease (PD) drug candidate, which can penetrate the Blood Brain Barrier (BBB) and recover the damaged dopaminergic (DA) neurons. It is a Therapeuticmolecule Systemic Delivery Technology (TSDT) applied Cell-/Tissue-permeable Parkin recombinant protein. Like endogenous Parkin, iCP-Parkin can have cytoprotective action by recovering dysfunctional mitochondria through mitophagy and mitochondrial biogenesis. iCP-Parkin can reduce the accumulation of pathological α-Synuclein, thereby suppressing PD phenotypes. Currently, typical PD treatment such as L-Dopa employs symptom-relieving drugs replenishing the loss of Dopamine in brain, temporarily recovering patient’s abnormal motor function. Although the symptom maybe eased, it is not addressing

Therefore, the disease will get worse as time passes and side effects will be occurred.In contrast, iCP-Parkin has neuroprotection capability against PD-induced cellular stress,having a great potential as a disease-modifying therapy for PD biotherapeutics.

In AAV-α-Synuclein-induced PD mouse models, conducted in Severance Hospital and Cellivery, the behavior deficit was recovered with the treatment of iCP-Parkin, and the accumulation of pathological α-Synuclein was removed in the SN, with the recovery of tyrosine hydroxylase (TH) level.

Currently, in collaboration with Ildong Pharmaceutical CO., LTD, we are conducting preclinical R&D of iCP-Parkin at various global GROs and CMOs to move forward more rapidly to clinical development process.Also, Cellivery as a first-time grant recipient in South Korea, established iCP-Parkin research in support of Michael J. Fox Foundation (MJFF) for Parkinson’s Research (MJFF Program: No.14241. 2017. 07 ~ 2019. 03).

 

CV-07

PIPELINE | CV-07
CP-BMP2

No Carrier! Only Simple Injection For Bone Regeneration!

Bone is the only organ that dynamically undergoes continuous tissue remodeling throughout life and is one of the few organs that retains regenerative potential on adult life. Severe damages in bone tissue require local supply of osteogenic growth factors of TGF-β family including bone morphogenetic proteins (BMPs) during regenerative process. Mainly, BMP2 plays an important role in skeletal development and bone formation. Clinical trials with recombinant human (rh) BMP2 protein-based approaches have been applied to promote the healing of severe fractures (e.g., long-bone non-union, tibial fracture implant) and spinal fusion. However, there are a few drawbacks with the use of rhBMP2. Due to short retention time and low tissue integration in a body, ? use of rhBMP2 is expensive with multiple or high-dose of treatment. In addition, rhBMP2 protein-based approaches have numerous side-effects (e.g., ectopic bone formation) at pharmacological dosage and sometimes requires surgical procedure, because it does not have an effective delivery method.

Cell-permeable BMP2 (CP-BMP2), our TSDT-applied rhBMP2, can be rapidly delivered into neighboring cells and tissues near the injured site by local injection, without a carrier/scaffold or any surgical procedure, and reside in the damaged bone tissue for a longer period, addressing rapid degradation and clearance rate issues that exist with rhBMP2. CP-BMP2 significantly activated Smad osteogenic signaling and induced ALP strongly. In addition, CP-BMP2 showed great persistency and enhanced stability in blood plasma. We also found that CP-BMP significantly promoted bone-regeneration (8 folds higher) in murine calvaria critical-sized defect and equine hind limb defect models.

Utilizing bio-better therapeutics with TSDT, we are developing CP-BMP2 as a next-generation osteogenesis agent to enhance local bone healing in a cost-/patient-friendly way.

 

CV-08

PIPELINE | CV-08
CP-ΔSOCS3

The abnormal control of leptin, an adipocyte-secreted hormone controlling appetite, chronically causes morbid obesity as it accumulates excessive body fat.

On binding to leptin receptor (ObR) expressed in hypothalamic neurons, leptin evokes JAK/STAT signaling, and induces the expression of suppressor of cytokine signaling 3 (SOCS3) as a negative feedback regulator to maintain the homeostatic balance between food intake and fat accumulation. However, excessive leptin in obesity increases level of endogenous SOCS3 which promotes “leptin resistance” and disables the appetite-control by leptin. Due to this phenomenon, leptin-based therapeutic approach failed to effectively cure severely-obese patients, though it had previously been considered as an attractive anti-obesity strategy.

The goal of the project was to use advanced macromolecule transduction domain (aMTD) to deliver a competitive protein-based inhibitor to disrupt the binding of SOCS3 and ObR. Cell-permeable (CP) truncated SOCS3 recombinant protein (CP-ΔSOCS3) has been developed to overcome leptin resistance, and to investigate whether leptin-induced anti-appetite signals can be maintained for the treatment of severe obesity.

We observed that CP-ΔSOCS3 was efficiently delivered into cells and tissues includinghypothalamus by penetrating blood brain barrier (BBB), and directly interacted with ObR andenhanced leptin signaling in vitro and in vivo.

Diet-induced obese (DIO) mice treated with CP-ΔSOCS3 shows 26% of body weight decreased under the regular-fat diet (RFD) condition and 12% of body weight decreased under the high-fat diet (HFD) condition through regulating the expression of appetite regulatory marker and energy expenditure marker. In addition, CP-ΔSOCS3 improved fatty liver and reduced total cholesterol level of obese mouse. Furthermore, CP-ΔSOCS3 decreased the blood glucose level in DIO mice indicating that it may have therapeutic effect on type II diabetes. Therefore, we have successfully demonstrated the therapeutic applicability of CP-ΔSOCS3 fused to aMTD as a mechanism-specific anti-obesity agent to restore normal appetite as well as type II diabetes.

Currently, CP-ΔSOCS3 is in preclinical studies by performing process development, manufacturing, encapsulation and analytical method development at global CROs and CMOs.

 

CV-09

PIPELINE | CV-09
iCP-Cre

Genetically engineered mouse models are useful tools for studying gene functionsin vivo.The discovery of Cre recombinase from bacteriophage P1 to induce DNA sequence-specific recombination in mammalian cells has achieved big advances in mouse models.

Applications involving Cre recombination have included conditional mutagenesis, gene replacement and chromosome engineering in mice, and conditional gene expression. However, process of generating Cre-mediated genetically engineered mouse models is expensive and time consuming. Also, the use of site-specific recombination in genetic studies is often hampered by difficulties expressing the recombinase enzyme in specific-type of cells and the desired developmental stage. Moreover, even conditional mutants induced by tissue-specific Cre expression may interfere with tissue development, thus, precluding later studies in terminally differentiated cells.

To overcome the limitation, the delivery of proteins with cell-penetrating peptides (CPP) intocells across impermeable cell membranes has been proposed as an attractive strategy to dealwith genetically engineered mouse models to define gene functions. The directly introducedcell-permeable recombinant protein is likely to be much easier, quicker, and less cost than othermethods, such as using Cre mouse or viral delivery.

For this purpose, we havenewly invented improved cell-permeable (CP) Cre recombinant protein fused to novel hydrophobic CPP, aMTD, to greatly increase their solubility, yield, and efficiency of membrane penetrating ability. iCP-Cre recombinant proteins induced high levels of recombination in a variety of cultured cells and all tissues examined in various genetically engineered mice (ROSA26-LSL-LacZ, ROSA26-LSL-EYFP, ROSA26nT-nG, SOCS3f/f etc.) following intravenous (IV) or local administration for whole-body or organ-specific (brain, liver, kidney etc.) recombination in vivo.

The use of protein transduction using cell-permeable Cre recombinase for genome engineering in animalsprovides a rapid and efficient tools to define gene function in mouse models.

 

CV-10,11

PIPELINE | CV-10,11
iCP-RFs/Cas9

Terminally differentiated somatic cells can be reprogrammed to become induced pluripotent stem cells (iPSCs) by enforced expression of reprogramming factors (RFs) whichpromote self-renewal and render pluripotent cells leading to cellular differentiation. RFs contain 2 types of proteins, one for maintaining embryonic stem (ES) cells in a pluripotent state (OCT4, SOX2, and NANOG) and the other for promoting self-renewal and suppress cellular differentiation (CMYC, KLF4 and LIN28).

Based on this discovery, therapeutic approaches were developed by using autologous stem cells from patient-derived iPSCs without the ethical and graft rejection problems associated with using embryo-derived stem cells. Practically, the application of iPSCs to human regenerative medicine might require gene transfer to introduce RFs into somatic cells. Unfortunately, somatic cell reprogramming through gene transfer is relatively inefficient and is potentially mutagenic due to the genome integration of DNA-based expression vector. Other approaches that are not related toDNA-based expression vectors, such as, synthetic modified RNA and epigenetic regulation by chemical compounds are far from the practical application.

To overcome the limitation, we have newly invented improved cell-permeable RFsrecombinant proteins (iCP-RFs) fused to novel hydrophobic CPP, advanced macromoleculetransduction domain (aMTD), and solubilization domain (SD).

iCP-RFs induce stem cell-like colonies with high efficiency (0.01%~0.1%) and early colony formation with extension of self-renewal capacity and expression of stem cell-specific markers (OCT4, NANOG, TRA-1-60, TRA-1-81). Furthermore, by confirming that the stem cell-like colonies generated by iCP-RFs from stably differentiated teratoma of three germ layer, iCP-RFs have been shown to induce stem cells with complete pluripotent properties.

On the other hand, genome engineering is a technology for gene editing or repairingto recognize specific genetic sequence. This genome engineering technology is applicable tovarious fields, such as food, medical and research reagent. Especially, genome editingtechnology is used for therapeutic models to apply to therapy of genetic diseases.

The recent technology of CRISPR/Cas9 is powerful toolfor genome editing to repair disease-causing DNA mutations. However, a safe and efficient DNA delivery system are critical for guarantying the success of gene editing. Cell-permeable (CP) Cas9 with TSDT enables a simple treatment by gene editing with high cell-permeability. It is an innovative reagent that made it possible to be delivered into cells without DNA delivery. CP-Cas9 is increased in gene editing efficiency caused by intracellular transduction compared to previously used plasmid and mRNA system. These advantages of CP-Cas9 can be applied to gene modification as well as genetic research. CP-Cas9 also can be applied to stem cell therapy, which uses induced pluripotent stem cells (iPSC) for patients with genetic disorders.

Cas9 technology has been recently applied to disease-focused research through the production and characterization of patient-derived iPSCs from individuals with specific genetic diseases. The invention of induced iPSCs has greatly advanced translational research, especially with the generation of disease-derived human iPSCs. We believe CP-Cas9 will bring tremendous change forward in genetic transformation animal models, and even in stem cell research and therapy. Cellivery is open to out-licensing opportunities to institutions that want to begin research or development with CP-Cas9.

 

CV-14

PIPELINE | CV-14 

Ataxia is a neurodegenerative disease defined as an impaired voluntary coordination of muscle movement. Ataxia is mainly attributed to damages in the lesions of cerebellum, a part of the brain that is responsible for coordinating movement. Symptoms from the ataxia are serious and oftentimes cause weakness. Some types of ataxia related with genetic mutations can lead to an early death. Even though treatment for ataxia involves a combination of medication to reduce symptoms and to improve quality of life, these therapies have not shown substantial clinical improvement associated with neuronal loss.

CV-14 project is dealing with a special ataxia which is characterized by a monogenic autosomal recessive disease-causing a progressive neurogenerative disorder and cardiomyopathy, leading to an early death. CV-14 protein is known to play a key role in iron metabolism, particularly in iron-sulfur cluster (ISC) biogenesis and heme biosynthesis in mitochondria. A deficiency of CV-14 protein leads to an iron-sulfur cluster biosynthesis dysfunction, mitochondrial iron overload and oxidative stress in neurons and cardiac muscles. Protein replacement therapy that delivers proteins into cells across impermeable cell membrane has been proposed as an attractive strategy to deal with genetic diseases. For this reason, Therapeuticmolecule Systemic Delivery Technology (TSDT) applied cell-permeable CV-14 protein has been developed to be systemically delivered into damaged neurons and cardiomyocytes to protect from ataxia.

CV-14 project will be an effective therapeutic approach to strengthen neuronal function, which will greatly help patients who are suffering from ataxia.

 

CV-15

PIPELINE | CV-15
iCP-NI

Sepsis is one of the top 5 diseases leading death worldwide and widely recognized as a clinical syndrome, resulting from an overwhelming, systemic inflammatory response.

Sepsis is occurred by excessive secretion of pro-inflammatory cytokine called ‘cytokine storm’, caused by microbial infection, severe injuries or surgical stresses. The global incidence of sepsis is 30 million and its overall mortality is more than 20 %, meaning that there are 6 million of death caused by sepsis every year. Besides, sepsis treatment is not adequately controlled by current antimicrobial therapies and supportive measures, thereby requiring new adjunctive treatments.

Previously, a polypeptide suppressing various pro-inflammatory pathways caused byendotoxamia has been developed by synthesizing the 1’st generation hydrophobic cell-penetratingpeptide (CPP), termed membrane translocating sequence (MTS) derived from the signal peptideof fibroblast growth factor 4 (FGF4), along with NF-κB-derived nuclear localization sequence (NLS).

Cell-permeable nuclear import inhibitor (CP-NI) increased survival rate of severe acute inflammatory animals by suppressing expression of pro-inflammatory cytokines such as TNF-α, IL-6 and IFN-γ. However, CP-NI was hard to manufacture mainly due to its low solubility, resulting in low clinical applicability. To address this limitation, improved cell-permeable nuclear import inhibitor (iCP-NI) has been developed by adopting advanced macromolecule transduction domain (aMTD) and demonstrated its superior stability and activity in sepsis animal models. iCP-NI successfully inhibits the activation of pro-inflammatory pathways and suppress secretion of pro-inflammatory cytokines. In addition, iCP-NI showed dramatically increased survivability in acute severe sepsis mouse models by protecting organ failure. Efficacy study with additional clinical animal models and safety study are on process to prove the powerful therapeutic applicability of iCP-NI.

As a result, this enhanced therapeutics, iCP-NI, can be developed as a novel, unique measures for severe lethal inflammatory syndromes such as septic shock.

 

CV-16

PIPELINE | CV-16

Single-chain variable fragment (scFv) consists of the smallest functional antigen-binding domain of an antibody,in which variable heavy and variable light chains are joined together by a flexible peptide linker.

scFv retains the binding specificity of the parent antibody and offer several advantages over monoclonal antibodies.scFv displays improved pharmacokinetic properties, such as better tissue penetration, rapid blood clearance, and lowimmunogenicity which makes better therapeutic agents.

Although scFv has higher tissue penetration compared to antibodies, it still requires deliverytechnology for higher efficacy. Delivering scFv to targeting area is one of the main obstacles indeveloping scFv as a therapeutic candidate. To intracellularly localize scFv, many researchorganizations have tried variety delivery technologies such as nanoparticles, adeno-associatedvirus (AAV), and cell-penetrating peptides. Cellivery applied its technology TherapeuticmoleculeSystemic Delivery Technology (TSDT) to scFv and developed Cell-Permeable CV-16

Despite various advantages of scFv, it has obstacles to become a therapeutic agent due to the lack of a suitable means of delivery.CV-16 will provide efficient and effective delivery system to intracellularly localize scFv in targeted cells for its highest efficacy.CV-16 will expand applications of scFv which will ultimately help patients in need.

 

CV-17

PIPELINE | CV-17

Antisense oligonucleotides (ASOs) are short, single-stranded oligodeoxynucleotide that interact with complementarymessenger RNA (mRNA) to prevent translation of a targeted gene into protein.

Thus, synthesizing an antisense oligonucleotide with the complementary sequence can be a drug which represent to work by binding to RNA. ASOs can reduce, restore, or modify protein expression through several distinct mechanisms by designing any sequences of RNA, so it can apply to treat a vast array of diseases.

Intracellular delivery of ASOs is recognized as the major barrier to effective ASOactivity within the target cell.

Therefore, to improve poor cellular uptake process, Cellivery used its technology Therapeuticmolecule Systemic Delivery Technology (TSDT) to improve cell-/tissue-permeability of ASOs. CP-17 can represent a new and valid approach to regulate the expression of disease-related genes and will greatly helpful for patients who are suffering from varying diseases.

 

R&D

OVERVIEW

Research
&
Development

PROPRIETARY
TECHNOLOGY

The plasma membrane acts as an impermeable barrier, controlling the flow of proteins and other macromolecules in and out of cells.

However, Cellivery’s proprietary Therapeuticmolecule Systemic Delivery Technology (TSDT) allows functionally active macromolecules to rapidly transverse cellular membranes. The process utilizes specialized Cell-Penetrating Peptides (CPPs) that can be engineered into peptides, whole proteins, DNA fragments, and other bioactive substances, such as, drugs. With additional subcellular trafficking signals, transduced macromolecules can be guided to specific cellular locations, providing an effective way to influence intracellular protein function.

Indeed, TSDT platform has attracted vast interest and commentary by individuals outside of the Company for its potential use in a variety of applications. We anticipate that many activities throughout the biotechnology industry will involve licensing of Cellivery’s TSDT platform.

A series of papers published by Dr. Daewoong Jo and his colleagues have described a process, termed TSDT, to deliver biologically active proteins into mammalian cells and tissues. The technology provides a way to control biochemical processes in living cells quantitatively and under non-steady conditions. This sets the stage for the development of a new generation of protein-based therapeutics.

Since proteins function with specificity in the context of cellular biochemical pathways, protein-based therapies are expected to produce fewer side-effects than conventional small molecule-based drugs. TSDT exploits the ability of hydrophobic sequences termed macromolecule transduction domains (MTDs) to promote the uptake of peptides and proteins into mammalian cells. Consequently, MTD-fused recombinant proteins are said to be “cell-permeable (CP)”.

TSDT has proven to be superior to other protein transduction technologies. In particular, the use of HIV Tat and other basic sequences that promote unidirectional protein uptake via fluid-phase and adsorptive endocytosis. This sequesters most proteins in intracellular vesicles, which traps the protein cargo inside the cell, limiting cytoplasmic delivery, resulting in low bioavailability.

Finally, proteins modified with MTD sequences had significantly prolonged clearance times as compared to the identical proteins without an MTD sequence.

 

PUBLICATION

"Founder’s Publication as the Corresponding Author (2011 ~ )"

01020304050607080910

Choi YS and Jo D, et. al. (2018) Cell-permeable parkin suppresses Parkinson disease phenotypes by promoting mitophagy and α-Synuclein clearance, Under Review
Shin SM and Jo D, et. al. (2019) Intracellular delivery of SOCS3 suppresses cancer & inflammation by inhibiting JAK/STAT signaling, Manuscript Under Preparation
Chung EN and Jo D, et. al. (2019) Cell-permeable bone morphogenetic protein 2 (CP-BMP2) alone enhances osteogenesis without a bone scaffold, Manuscript Under Preparation
Lee SY and Jo D, et. al. (2019) Epigenetic regulation of gene structure and function with improved cell-permeable Cre recombinase (iCP-Cre) for site-specific recombination in genetically engineered animals, Manuscript UnderPreparatio
Duong T, Kim J, Ruley HE and Jo D (2014) Cell-permeable parkin proteins suppress parkinson disease- associated phenotypes in cultured cells and animals, PLoS ONE, 2014 Dec 17;9(12):e116242.
Lim J*, Kim J*, Kan g J and Jo D (2014) Partial somatic to stem cell transformations with cell- permeable reprogramming factors, Scientific Reports, 2014 Mar 12;4:4361-4371.
Lim J*, Duong T*, Lee G, Seong BL, El-Rifai W, Ruley HE and Jo D (2013) The effect of intracellular protein delivery on the anti-tumor activity of recombinant human endostatin, Biomaterials, 2013 Aug 1;34(26): 6261-71. Epub 2013 May 25.
Lim J, Duong T, Do N, Do P, Kim J, Kim H, El-Rifai W, Ruley HE and Jo D (2012) Antitumor activity of cell-permeable RUNX3 protein in gastric cancer cells, Clinical Cancer Research, 2013 Feb 1;19(3):680-690. Epub 2012 Dec 10.
Lim J, Kim J, Duong T, Lee G, Kim J, Yoon J, Kim J, Kim H, Ruley HE, El-Rifai W and Jo D (2012) Antitumor activity of cell- permeable p18INK4c with enhanced membrane and tissue penetration. Molecular Therapy, 2012 Aug;20(8):1540-1549. Epub 2012 May 22.
Lim J, Jang G, Kang S, Lee G, Nga DT, Phuong DT, Kim H, El-Rifai W, Ruley HE and Jo D (2011) Cell permeable NM23 blocks the maintenance and progression of established pulmonary metastasis. Cancer Research, 2011 Dec 1;71(23):7216-25. Epub 2011 Oct 10.

"Founder’s Publication as the First or Co-Author (2001 ~ )"

0102030405060708

Ock S, Ahn J, Lee SH, Kang H, Offermanns S, Ahn HY, Jo YS, Shong M, Cho BY, Jo D, Abel ED, Lee TJ, Park WJ, Lee IK, Kim J (2013) IGF-1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH-stimulated goiter, FASEB Journal, 2013 Dec;27(12):4899-4908. Epub 2013 Aug 27.
Jeon D, Kim S, Chetana M, Jo D, Ruley HE, Lin SY, Rabah D, Kinet JP, Shin HS (2010) Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC, Nature Neuroscience, 2010 Apr;13(4):482-8. Epub 2010 Feb 28.
Kee H, Eom G, Joung H, Shin S, Kim J, Cho Y, Choe N, Sim B, Jo D, Jeong M, Kim K, Seo J, Kook H (2008) Activation of histone deacetylase2 by inducible Hsp70 in cardiac hypertrophy. Circulation Research, 2008 Nov 21;103(11):1259-69. Epub 2008 Oct 10.
Lin Q, Jo D, Gebre-Amlak KD and Ruley HE (2004) Enhanced cell-permeant Cre protein for site-specific recombination in cultured cells. BMC Biotechnology, 2004 Oct 22;4(25):1-13
Jo D, Liu D, Yao S, Collins RD and Hawiger J (2005) Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nature Medicine, 2005 Aug;11(8):892-8. Epub 2005 Jul 10.
Jo D, Leren T, Yang Z, Chung Y, Taylor JM and Paik YK (1995) Characterization of an upstream regulatory element of the human apolipoprotein E gene, and purification of its binding protein from the human placenta. Journal of Biochemistry, 1995 Apr;117(4):915-22.
Jo D, Lin Q, Nashabi A, May D, Unutmaz D, Pietenpol JA and Ruley HE (2003) Cell cycle-dependent transduction of cell-permeant Cre recombinase proteins. Journal of Cellular Biochemistry, 89(4):674-687
Jo D, Nashabi A, Doxsee D, Lin Q, Unutmaz D, Chen J and Ruley HE (2001) Epigenetic regulation of gene structure and function with a cell permeable Cre recombinase. Nature Biotechnology, 19(10):929-933

"Selected Publications of Dr. Ruley"

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Ruley HE, 1983, Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature, (5927)304: p. 602-6
Ruley HE and, Fried M, 1983, Clustered illegitimate recombination events in mammalian cells involving very short sequence homologies. Nature, (5922)304: p. 181-4
Cook JL and Ruley HE, et al., 1986, Expression of the adenovirus E1A oncogene during cell transformation is sufficient to induce susceptibility to lysis by host inflammatory cells. Proc Natl Acad Sci U S A, (18)83: p. 6965-9
Franza BR, Jr. and Ruley HE, et al., 1986, In vitro establishment is not a sufficient prerequisite for transformation by activated ras oncogenes. Cell, (3)44: p. 409-18
Hirakawa T and Ruley HE, et al., 1988, Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene. Proc Natl Acad Sci U S A, (5)85: p. 1519-23
Von Melchner H and Ruley HE, et al., 1990, Isolation of cellular promoters by using a retrovirus promoter trap. Proc Natl Acad Sci U S A, (10)87: p. 3733-7
Reddy S and Ruley HE, et al., 1992, Fluorescence-activated sorting of totipotent embryonic stem cells expressing developmentally regulated lacZ fusion genes. Proc Natl Acad Sci U S A, (15)89: p. 6721-5
Von Melchner H and Ruley HE, et al., 1992, Selective disruption of genes expressed in totipotent embryonal stem cells. Genes Dev, (6)6: p. 919-27
Lowe SW and Ruley HE, et al., 1993, Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev, (4)7: p. 535-45
DeGregori J and Ruley HE, et al., 1994, A murine homolog of the yeast RNA1 gene is required for postimplantation development. Genes Dev, (3)8: p. 265-76
Lowe SW and Ruley HE, et al., 1994, Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. Proc Natl Acad Sci U S A, (6)91: p. 2026-30
Martin WD Ruley HE, et al., 1996, H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection. Cell, (4)84: p. 543-50
Hicks GG and Ruley HE, et al., 1997, Functional genomics in mice by tagged sequence mutagenesis. Nat Genet, (4)16: p. 338-44
Hicks GG and Ruley HE, et al., 2000, Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet, (2)24: p. 175-9
Jo D and Ruley HE, et al., 2001, Epigenetic regulation of gene structure and function with a cell-permeable Cre recombinase. Nat Biotechnol, (10)19: p. 929-33
Osipovich AB and Ruley HE, et al., 2005, Post-entrapment genome engineering: first exon size does not affect the expression of fusion transcripts generated by gene entrapment. Genome Res, (3)15: p. 428-35
Donahue SL and Ruley HE, et al., 2006, Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability. Proc Natl Acad Sci U S A, (31)103: p. 11642-6

Osipovich AB and Ruley HE, et al., ., 2008, Dyggve-Melchior-Clausen syndrome: chondrodysplasia resulting from defects in intracellular vesicle traffic. Proc Natl Acad Sci U S A, (42)105: p. 16171-6

 

INTELLECTUAL PROPRIETARY

"Cellivery is Patentee"

#TargetIndication and UseApplication NumberDateRegistration Number/Date

01 aMTDs aMTD/TSDT Platform
[PCT/KR2015/008544]
CN (201580044116.8) 17.02.16
JP (2017-510405) 17.02.15 6559227 (19.08.14)
US (15/503117) 17.02.10 10323063 (19.06.18)
CA (2957501) 17.02.07
KR (10-2017-7005079) 17.02.22 101971021 (19.04.23)
EP (15833496.1) 17.02.13
AU (2015304194) 17.01.12 2015304194 (18.03.01)
02 iCP-SOCS3
Pancreatic Cancer Therapy
[PCT/KR2016/009416]
EP (16839623.2) 18.03.13
US (15/408123) 17.01.17
Solid Tumor Therapy
[PCT/KR2016/009414]
EP (16839621.6) 18.03.15
US (15/361701) 16.11.28
Anti-Angiogenesis Therapy
[PCT/KR2016/009456]
EP (16839637.2) 18.03.16
US (15/631982) 17.06.23
Hepatocellular Carcinoma Therapy
[PCT/KR2016/009446]
US (15/432662) 17.02.14 10385103 (19.08.20)
Lung Cancer Therapy
[PCT/KR2016/009441]
US (15/408230) 17.01.17
03 iCP-Parkin Parkinson's Disease Therapy
[PCT/KR2016/008174]
CN (201680044600.5) 18.04.03
JP (2018-503759) 18.01.25
US (15/879664) 18.01.25
CA (2993778) 18.01.25
KR (10-2018-7005889) 18.02.27
EP (16830820.3) 18.02.27 등록완료/등록번호 미정
AU (2016299468) 18.01.17 2016299468(19.07.25)
IN (201827002920) 18.01.24
04 CP-BMP2 Bone Healing Therapy
[PCT/KR2016/009405]
EP (16839619.0) 18.03.12
US (15/884884) 18.01.31 등록완료/등록번호 미정
05 CP-△SOCS3 Obesity Therapy
[PCT/KR2016/008831]
EP (16837265.4) 18.03.07
US (15/888459) 18.02.05 10323072 (19.06.18)
06 iCP-Cre Genome Engineering Enzyme
[PCT/KR2016/008760]
EP (16835419.9) 18.03.02
US (15/887414) 18.02.02
07 iCP-RFs iPSC Reprogramming Factors
[PCT/KR2016/008757]
EP (16835416.5) 18.03.02 등록완료/등록번호 미정
US (15/884651) 18.01.31 등록완료/등록번호 미정
08 CP-Cas9 Genome Editing Enzyme
[PCT/KR2017/010747]
EP (17856752.5) 19.03.14
US (16/337250) 19.03.27

 

 

 

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