Keytruda / LoD-LLOQ / [GT] AAV / Capsid (serotype)

• MSI-H identified by IHC (deficiency of MLH1, MSH2, MSH6, or PMS2), or by PCR (instability in ≥2 loci)
• Primary endpoint: ORR
• Secondary endpoints: PFS by RECIST v1.1, and OS

Preclinical	Clinical POC	Expansion of POC
Js, no description at all
	(Le et al. 2015, PMID 26028255) NCT01876511	(Le et al. 2017, PMID)
PATIENTS	41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency	N=11 (focused), CRC
Findings	CRC with MMR deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1).
Additional findings		Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific Tcell clones that were reactive to mutant neopeptides found in the tumor (js, this analysis was done in three responsive patients comparing preTx & postTx

• LoD: the lowest concentration at which 95% of positive samples are detected.
• LLOQ:
  • QL = 10σ/S [1]
  • lower limits of quantification (LLOQ)
  • the lowest analyte concentration that can be quantitatively detected with a stated accuracy and precision, the lowest standard on the calibration curve.
  • Js: LLOQ seems more important than LOD
  • LOD can be lower than LLOQ

[GT]

Scheme of a CMV virus

AAV

그런데, AAV 가 Coat 가지고 있는지 잘 모르겠음.

Schaffer DV, et al. 2008. Annu. Rev. Biomed. Eng. 10:169–94.

single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids.

Capsid (serotype)

Tissue tropism

바이러스의 유전체핵산을 둘러싸는 단백질의외각으로 규직적으로 배열하는 다수의 단위소립자, 즉 캡소머로 구축되어 있는 것이다.

기본적 형태는 캡소머의 나사모양배열에 의해 생기는 원주상인 것(담배모자이크바이러스 등)과 등방성 배열에 의해서 생기는 정20면체의 것(아데노바이러스)이있다

Serotype	AAV5	AAV9
Primary receptor	α2,3 N-linked Sialic Acid	Galactose
CNS tropism	Neurons, glia	Neurons, glia
Intracranial Delivery (CSF or parenchymal): Neuronal transduction	++	+++
Intracranial Delivery (CSF or parenchymal): Glial transduction	+	++
Intravascular: Neuronal transduction	-	+++
Intravascular: Glial transduction	-	+++
Precedence	Precedence: UniQure, Krys Bankiewicz (UCSF), Guangping Gao (UMMS), Bev Davidson (CHOP)	Precedence: Zolgensma (Avexis) Preferential transduction of hindbrain after IV or IT-L

{Castle, 2016 #2473} AAV serotypes 1, 2, 6, 7, 8, and 9 transduce both neurons and astrocytes in primary culture [16, 17]. Following intraparenchymal brain injection, AAVs 1, 2, 5, 7, 8, 9, and rh.10 all exhibit strong neuronal tropism, as gene expression rarely colocalizes with markers for astrocytes or oligodendrocytes [18–21]. However, others have observed astroglial transduction with AAVs 1, 2, 5, 6, and 8 [22–24].

1/2 appears to combine the tropism of AAV2 for TH-positive dopamine neurons with the ability of AAV1 to diffuse more widely through brain tissue, indicating strong transduction of dopamine neurons in the substantia nigra, and has been used to model Parkinson’s disease in the rat [70]

2/5 indicates a virus containing the genome of serotype 2 packaged in the capsid from serotype 5

	Biodistribution	Administration route
AAV9	CNS, Only VG data published	ICM	Prevail Tx (Passage Bio, REGENXBIO)

Uncertain Spans

location	text/status	reason
(Le et al. 2017, PMID)	missing PMID	The PMID number is not visible in this photo; only the placeholder PMID remains.
Additional findings cell	trailing parenthesis	Closing ) is not visible at the visible right edge; preserved as written.
Korean caption	규직적으로	Likely a typo of 규칙적으로; preserved as visible.
Bottom biodistribution table	next row	Lower row(s) of the red Biodistribution / Administration route table cut off at the bottom edge.