Caribou Biosciences, Inc.

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CRBU

US1420381089

Biotechnology & Medical Research

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May. 09	Truist Adjusts Price Target on Caribou Biosciences to $19 From $21, Maintains Buy Rating	MT
May. 07	Caribou Biosciences, Inc. Reports Earnings Results for the First Quarter Ended March 31, 2024	CI

Caribou Biosciences : Cas12a chRDNA in vivo editing ASGCT 2024

May 10, 2024 at 12:15 pm EDT

May 10, 2024

Cas12a CRISPR Hybrid RNA-DNA (chRDNA)- Mediated In Vivo Genome-Editing Technology for Efficient and Functional Hepatic Gene Disruption

27th American Society of Cell & Gene Therapy (ASGCT) Annual Meeting Baltimore, MD

Development of a Cas12a-mediatedin vivo editing platform

CRISPR nucleic acids

Gene vector	Cas12a	Guide
mRNA
In vivo delivery	in vivo

		platform

LNPs

ASGCT Annual Meeting | May 10, 2024

2 LNP: lipid nanoparticles

mRNA optimization for in vivo applications

	Promoter	RNA coding sequence
DNA
	Cap		Transcription		Poly(A) tail

pre-mRNA	5'	Exon	Exon	Exon	AAAAAAAAAA…. 3'
	5' UTR	Intron	Intron		3' UTR
			RNA Splicing
mRNA 5'	5' UTR	Protein-coding region	3' UTR	AAAAAAAAAA…. 3'

5'-CAP	5'UTR	Cas12a	3'UTR
	Mammalian	Uridine	Full N1-
	methylpseudouridine
	codon optimized	depleted
	substituted

Cas12a

mRNA Guide

LNPs

pA(120)

3	UTR: untranslated region; pA(120): 3'-end poly(A) tail, 120 nucleotides	ASGCT Annual Meeting \| May 10, 2024
©2024 Caribou Biosciences, Inc.

Cas12a + CRISPR hybrid RNA-DNA (chRDNA) have improved specificity in vitro

Cas12a

mRNA Guide

LNPs

	Cas12a guides tolerate multiple types	Incorporation of DNA can rescue the activity
	of chemically-modified bases	of certain chemically-modified designs
	100			100
	80			80
%	60		%	60
Editing		Editing
40		40
	20			20
	0			0
	crRNA chem-mod	crRNA chem-mod		crRNA chem- chem-mod
	Target 1	Target 2		mod	+
			chRDNA
4	crRNA: CRISPR RNA guide; chRDNA: CRISPR hybrid RNA-DNA guide

Cas12a chRDNA guides have improved specificity compared to all-RNA guides

	100
	80
%	60

Editing	40

1.0

0.8

0.6

0.4

0.2

0.0

On Off On Off

crRNA chRDNA

Optimized chRDNA guides achieve peak activity across validated targets

Cas12a

mRNA Guide

LNPs

Gene targets

Ttr, Pcsk9, Angptl3

Guide identification

									Repeat													Spacer

1	2	3	4	5	6	7		8	9		10	11	12	13	14	15	16	17	18	19	20	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20

																		Iterative SAR
																					v1
										Chemical										Assessment for:
													v2							Activity
							modifications

																					v3							Off-targets

5 chRDNA: CRISPR hybrid RNA-DNA; Ttr: transthyretin gene; SAR: structure-activity relationship;

Normalized editing (%)

0 25 50 75 100 125 150

mps_D_21

mps_D_22

mps_D_23

mps_D_24

Pcsk9-tgt5

mps_D_25

Ttr-tgt9

Angptl3-tgt18

ASGCT Annual Meeting | May 10, 2024

In-house LNP formulation of ALC0315 drive higher expression at 24h compared to commercial formulation

Cas12a

mRNA Guide

In-house

ALC0315	SM102	MC3
ffLuc mRNA	ffLuc mRNA	ffLuc mRNA

(Photon/s)	Editing
window
GenVoy ffLuc mRNA
	Saline
Intensity	(1 mg/kg)
ALC0315 ffLuC mRNA
Bioluminescent	(1 mg/kg)
SM102 ffLuc mRNA

	(1 mg/kg)
	MC3 ffLuc mRNA
	(1 mg/kg)
	Days Post Treatment

Commercial
GenVoy	4.0
ffLuc mRNA

	3.0
	x109
	2.0
	1.0

Bioluminescent Intensity (Photon/s)

Saline

GenVoy ffLuc mRNA

ALC0315 ffLuc mRNA

LNPs

Radiance

(p/sec/cm2/sr)

Color scale

Min=5.25e7

Max=4.22e9

P-value symbols

ns	P > 0.05
*	P ≤ 0.05
**	P ≤ 0.01
***	P ≤ 0.001

**** P ≤ 0.0001

SM102 ffLuc mRNA

MC3 ffLuc mRNA

6 LNP: lipid nanoparticle; ffLuc mRNA: Firefly Luciferase mRNA

Reproducible platform for encapsulating mRNA + guides in LNPs

Cas12a mRNA was successfully encapsulated in LNPs	LNP size, polydispersity, and encapsulation
with either crRNA or chRDNA targeting Pcsk9, Ttr,
efficiency were in range for in vivo administration
or Angptl3 using ALC0315 in-house lipid mix

Z-Ave Diameter (nm)

Size
Upper limit before	(PDI)

immunogenic response	Polydispersity index

crRNAchRDNA

Pcsk9-tgt5Angptl3-tgt8Ttr-tgt9

Uniformity

In vivo

range

crRNAchRDNA

Encapsulation efficiency

(EE)	In vivo range
%Encapsulation Efficiency
chRDNA
crRNA

Transthyretin (TTR) amyloidosis

Pathobiology of transthyretin amyloid

Small

oligomers

Liver	Restrictive

	Cardiomyopathy

		Folded	Misfolded
		monomers	amyloidgenic	Amorphous	Amyloid
TTR mRNA	TTR tetramer	Folded dimers	monomers	aggregates
					fibrils

Rare disease (approx. 5/100,000 in 2018 in the US)1

Most common mutations: V122I (US), V30M (worldwide)1,2

Mutations in the Ttr gene cause amyloids to build up in the heart, nervous system, or both Survival post-diagnosis approx. 25 months2

Peripheral and/or

Autonomic Neuropathy

8	1Cleveland Clinic 2019, Amyloidosis Research Consortium, 2024	ASGCT Annual Meeting \| May 10, 2024
2Ruberg, F. L., et al. Journal of the American College of Cardiology, 73(22), 2872-2891	©2024 Caribou Biosciences, Inc.

Ttr multi-dose study design

tgt9

LNP Cas12a + guide	LNP Cas12a + guide
(2 mg/kg)	(2 mg/kg)

48h

1 Saline (4 mice)

Study	2	Cas12a mRNA + Ttr-tgt9-crRNA (4 mice)
groups

3 Cas12a mRNA + Ttr-tgt9-chRDNA (4 mice)

Ttr

LNP Cas12a + guide

(2 mg/kg)

12 days

Mouse strain: Balb/c	Injection volume: 400 µL
Age: 7 weeks	Administration: Primary
Dose: 3 x 2 mg/kg	intravenous (IV)

ASGCT Annual Meeting | May 10, 2024

In vivo liver editing of Ttr resulted in >98% knockdown of plasma TTR levels using both crRNA or chRDNA guides

% Edited

Liver editing

1500

1000 (ug/ml)TTR 500

Saline	Ttr-tgt9-	Ttr-tgt9-	0

	crRNA	chRDNA
	3x2mg/kg	3x2mg/kg

Plasma TTR

ns✱✱✱✱

✱✱✱✱

D16

Saline Ttr-tgt9-crRNATtr-tgt9-chRDNA

ASGCT Annual Meeting | May 10, 2024

10 ns/nd P > 0.05; * P ≤ 0.05; **** P ≤ 0.0001

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Caribou Biosciences Inc. published this content on 10 May 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 10 May 2024 16:14:09 UTC.

Latest news about Caribou Biosciences, Inc.

Truist Adjusts Price Target on Caribou Biosciences to $19 From $21, Maintains Buy Rating	May. 09	MT
Caribou Biosciences, Inc. Reports Earnings Results for the First Quarter Ended March 31, 2024	May. 07	CI
Sector Update: Health Care Stocks Lean Higher Pre-Bell Friday	Apr. 05	MT
Caribou Gets FDA Clearance For Phase 1 Testing of CB-010 Cell Therapy in Lupus Patients	Apr. 04	MT
Caribou Biosciences, Inc. Expands Clinical Development of CB-010 with FDA Clearance of IND in Lupus	Apr. 04	CI
Poseida Therapeutics Appoints Syed Rizvi as Chief Medical Officer	Mar. 25	MT
HC Wainwright Adjusts Caribou Biosciences Price Target to $24 From $23, Maintains Buy Rating	Mar. 19	MT
Caribou Biosciences, Inc. Reports Earnings Results for the Full Year Ended December 31, 2023	Mar. 11	CI
Caribou Biosciences, Inc. Reports Earnings Results for the Fourth Quarter and Full Year Ended December 31, 2023	Mar. 11	CI
Caribou Biosciences, Inc. Appoints Tim Kelly as Chief Technology Officer	Jan. 07	CI
North American Morning Briefing : Traders Await FOMC, Powell	Dec. 13	DJ
Caribou Biosciences Says it Reached Alignment With FDA on Phase 3 Trial Plan for Lymphoma Treatment	Dec. 13	MT
Caribou Biosciences Shares Rise 4.1% as FDA Approves Lymphoma Trial	Dec. 12	DJ
Syed Rizvi to Leave the Caribou Biosciences, Inc. as Chief Medical Officer, Effective from December 31, 2023	Dec. 12	CI
Caribou Biosciences Provides Regulatory Update on CB-010 Pivotal Plan with Phase 3 Trial Initiation Expected by YE 2024	Dec. 12	CI
Cantor Fitzgerald Initiates Caribou Biosciences at Neutral Rating	Nov. 08	MT
Caribou Biosciences, Inc. Reports Earnings Results for the Third Quarter and Nine Months Ended September 30, 2023	Nov. 07	CI
Caribou Biosciences, Inc. Appoints Sundar Jagannath to its Scientific Advisory Board	Nov. 06	CI
US FDA Clears Caribou Biosciences' CB-012 Cancer Drug Candidate for Human Study	23-10-18	MT
Caribou Biosciences, Inc. Announces FDA Clearance of IND Application for CB-012, an Allogeneic Anti-CLL-1 CAR-T Cell Therapy for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia	23-10-18	CI
Caribou Biosciences, Inc. Appoints Reigin Zawadzki as Chief People Officer	23-09-27	CI
AbbVie Elects to Terminate the Collaboration and License Agreement with Caribou Biosciences, Inc	23-09-26	CI
Caribou Biosciences, Inc.(NasdaqGS:CRBU) added to S&P Biotechnology Select Industry Index	23-09-18	CI
Certain Restricted Stock Units of Caribou Biosciences, Inc. are subject to a Lock-Up Agreement Ending on 12-SEP-2023.	23-09-11	CI
Certain Stock Options of Caribou Biosciences, Inc. are subject to a Lock-Up Agreement Ending on 12-SEP-2023.	23-09-11	CI

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Company Profile

Caribou Biosciences, Inc. is a clinical-stage clustered regularly interspaced short palindromic repeats (CRISPR) genome-editing biopharmaceutical company. It is engaged in developing transformative therapies for patients with devastating diseases. Its genome-editing platform, including its Cas12a chRDNA technology, enables precision to develop cell therapies that are armored to potentially improve antitumor activity. Its pipeline includes three clinical-stage allogeneic cell therapies from its chimeric antigen receptor (CAR)-T (CAR-T) cell platform targeting the treatment of hematologic malignancies. CB-010 is the lead product candidate from its allogeneic CAR-T cell therapy platform and is being evaluated in patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL). Its second product candidate, CB-011, is being evaluated in patients with relapsed or refractory multiple myeloma (r/r MM) in the CaMMouflage phase I trial. CB-012 is its third product candidate.

Sector

Biotechnology & Medical Research

Calendar

2024-06-02 - American Society of Clinical Oncology Annual Meeting - Abstract number: CB-010

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Analysts' Consensus

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Mean consensus

BUY

Number of Analysts

Last Close Price

3.01 USD

Average target price

19.75 USD

Spread / Average Target

+556.15%

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