Recent Advances In Hematology 2022 ADCs, Bispecific Antibodies, CAR-T Cells…

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Recent Advances In Hematology 2022: ADCs,
Bispecific Antibodies, CAR-T Cells…

Several innovative therapies are now available for hematology disorders, including six
CAR-T therapies that have received FDA approval. There are also three of the five
bispecific antibodies currently approved globally for the treatment of hematology
disorders, including Lunsumio, which received EU approval in June 2022. In this article,
we will share with you the latest advances in innovative hematology therapies.

Antibody Drug Conjugates (ADCs) for
Hematology

Antibody drug conjugates (ADCs) represent a new class of novel targeted agents with
significant improvement in therapeutic efficacy in the treatment of hematological
malignancies. Several of these agents, which offer improved targeting, greater potency,
and better therapeutic index over traditional chemotherapy, are changing the treatment
landscape for hematological malignancies.

Multiple ADCs have been approved by the FDA for clinical use in hematological
malignancies in the U.S. which include: gemtuzumab ozogamicin (a CD33-targeting
agent approved for acute myeloid leukemia), brentuximab vedotin (a CD30-targeting
agent approved for HL and anaplastic large cell lymphoma), inotuzumab ozogamicin (a
CD22-targeting agent approved for acute lymphoid leukemia) and polatuzumab
vedotin (a CD79-targeting agent approved for NHL).

Camidanlumab Tesirine (Cami)

Recently in EHA 2022 online congress, ADC Therapeutics announced the latest results
from a pivotal phase 2 clinical trial of the investigational ADC camidanlumab tesirine

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(Cami) for the treatment of patients with relapsed/refractory Hodgkin's lymphoma. Cami is
generated by coupling a monoclonal antibody targeting CD25 with a
pyrrolobenzodiazepine dimer (PBD). Once bound to a cell expressing CD25, it gets
endocytosed. There, the protease releases a PBD-based payload that kills the cell. This
process may also kill neighboring tumor cells and has also been shown to induce
immunogenic cell death. All of these properties of Cami may enhance immune-mediated
antitumor activity.

Figure 1. Structure of Camidanlumab Tesirine

The latest results showed that Cami achieved an objective remission rate of 70.1% and a
complete remission rate of 33.3% in patients who received a median of six prior therapies.
The median duration of remission was 13.7 months and the median progression-free
survival (PFS) was 9.1 months. Based on these results, the company is preparing to
submit a biologics license application for Cami to the U.S. FDA.
By the way, the Camidanlumab Tesirine applies a monodisperse PEG derivatives ad its
linker. Biopharma PEG offers a variety of PEG linkers to facilitate ADC development
projects. All PEG linkers are of >95% purity and they are the basic building blocks for a
successful ADC.

Polivy & R-CHP

Roche has announced the results of a subgroup analysis of the Phase 3 clinical trial of its
ADC therapy Polivy in combination with a regimen called R-CHP for the first-line treatment

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of diffuse large B-cell lymphoma (DLBCL). The combination therapy was
recently approved by the European Commission to treat patients with primary DLBCL.

The published subgroup analysis of Asian participants showed that Polivy, in combination
with R-CHP, reduced patients' risk of disease progression, relapse or death by 36%
compared to standard treatment regimens (HR=0.64, 95% CI: 0.40-1.03).

CAR-T Cell Therapy For Hematology

Chimeric antigen receptor T-cell (CAR-T) therapy, in which T-cells are genetically
modified to recognize and proliferate in response to tumor antigens, is revolutionizing the
treatment of hematologic malignancies. Since 2017, six CAR T-cell therapies have
been approved by the Food and Drug Administration (FDA). All are approved for the
treatment of blood cancers, including lymphomas, some forms of leukemia, and, most
recently, multiple myeloma.

Table 1: FDA Approved CAR-T Cell Therapies

CB-010

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Caribou Biosciences, co-founded by Dr. Jennifer Doudna, a Nobel Prize winner and
pioneer in CRISPR, announced the latest clinical trial results of CB-010, an off-the-shelf
CAR-T therapy made using CRISPR gene-editing technology. This CAR-T therapy uses
CRISPR gene editing to knock out the PD-1 receptor expressed by T cells and is
designed to improve the durability of cellular therapies.

Figure 2. Preliminary efficacy results of CB-010 (Image source: Caribou Biosciences
website)

Results from the latest clinical trial showed that CB-010 achieved a 100% complete
remission rate in six patients with relapsed/refractory B-cell non-Hodgkin's lymphoma
treated with the initial dose of CB-010. After 6 months, the complete remission rate was
40%. One patient remained in complete remission after 12 months of treatment.

Based on these results, Caribou plans to enroll the next cohort of patients to receive a
higher dose of CB-010.

WU-NK-101

Wugen presented preclinical data on its investigational memory NK cell therapy,
WU-NK-101, at the EHA Congress. The company's memory NK cells offer enhanced

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tumor-killing ability and in vivo persistence compared to conventional NK cell therapies,
promising a new therapy with improved efficacy and a favorable safety profile.

Data from preclinical studies presented at the EHA Congress showed that WU-NK-101
was effective in reducing tumor load in a mouse model of acute myeloid leukemia (AML)
when administered as single or multiple doses. These data support clinical trials in
patients with relapsed/refractory AML.

WU-NK-101 exhibits both improved activation, metabolic flexibility, and enhanced
cytotoxicity. It also exhibited improved metabolic health and adaptability in the
immunosuppressed tumor microenvironment compared to conventional NK cell therapies,
supporting its application in solid tumors.

CRISPR/Cas9

Vor Bio announced that using CRISPR/Cas9 technology, it has successfully completed
dual gene editing in human hematopoietic stem cells, knocking out the expression of both
CD33 and CLL-1. Human hematopoietic stem cell transplantation is one of the important
options for treating AML patients. However, while targeted therapies for AML can kill
cancer cells, they can also kill healthy hematopoietic cells and produce toxic side effects,
Vor Bio's strategy is to knock out the drug-targeted targets in healthy hematopoietic stem
cells through gene editing. This is like putting a "cloak of invisibility" on healthy cells so
that they cannot be accidentally injured by drugs. Targeted therapies can then be freed up
to focus on tumor cells, increasing their specificity while reducing their potential side
effects.

This result not only shows the feasibility of multiple gene editing in hematopoietic stem
cells, but also indicates that knockdown of CD33 and CLL-1 does not affect the normal
function of the cells. Coupling this cell transplantation therapy with targeted therapies may
provide a better treatment option for AM.

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Bispecific Antibodies For Hematology

Bispecific antibodies (bsAb) that target two independent epitopes or antigens and can
thereby exert two different functions. They are currently used to treat infectious,
inflammatory, and malignant diseases. Currently, there are five bispecific
antibodies that have received market approval, of which 3 are approved for the
treatment of hematological malignancies, including Blincyto (blinatumomab),
Hemlibra (emicizumab) and Lunsumio (faricimab-svoa).

Table 2. Approved bispecific antibodies

Teclistamab

Janssen announced at the EHA Congress the results of a clinical trial of its BCMA/CD3
bispecific antibody therapy, teclistamab, in combination with the subcutaneously
administered anti-CD38 antibody daratumumab, for the treatment of patients with multiple
myeloma who have received at least three prior therapies.

At a median follow-up time of 8.6 months, 76.5% of evaluable patients achieved remission
and 70.6% achieved very good partial remission (VGPR) or better. Objective remission
rates also reached 73.7% in the subgroup of patients who had been treated with
anti-CD38 antibodies. The researchers said that the patients who achieved remission

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included those previously treated with BCMA or CD38-targeted therapies, implying that
this steroid-free immune combination therapy may present an effective treatment option
for highly refractory patients.

Targeted Therapies

AbbVie announced the results of a Phase 2 clinical trial of its investigational
BCL-XL/BCL-2 inhibitor navitoclax, in combination with ruxolitinib, in patients with
myelofibrosis who have not been treated with a JAK inhibitor. BCL-2 family proteins are
important regulators of the apoptosis pathway, and by inhibiting BCL-XL/BCL-2,
navitoclax may promote cancer cell death.

Results from this phase 2 clinical trial showed that after 24 weeks of treatment, 63% of the
32 evaluable patients met the trial's primary endpoint, defined as a reduction in spleen
volume of more than 35%. The trial also met the critical secondary endpoint, with 41%
(11/27) of evaluable patients experiencing more than a 50% reduction in total symptom
scores at week 24.

This study demonstrates the anti-fibrotic activity of a combination therapy consisting of
navitoclax and ruxolitinib, supporting intervention in the early stages of myelofibrosis and
improving clinical outcomes for patients.

References:
[1] ADC Therapeutics Announces Results from Pivotal Phase 2 Clinical Trial of Camidanlumab Tesirine
(Cami) in Relapsed or Refractory Hodgkin Lymphoma. Retrieved June 10, 2022,
from https://www.businesswire.com/news/home/20220610005073/en
[2] Wugen Presents New Preclinical Data Demonstrating Enhanced Anti-Tumor Activity of WU-NK-101 at
the European Hematology Association (EHA) 2022 Hybrid Congress. Retrieved June 10, 2022,
from https://www.businesswire.com/news/home/20220610005107/en
[3] Caribou Biosciences Reports Positive Additional Data from CB-010 Allogeneic CAR-T Cell Therapy

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Phase 1 ANTLER Trial at the European Hematology Association (EHA) 2022 Hybrid Congress.
Retrieved June 10, 2022,
from https://www.globenewswire.com/news-release/2022/06/10/2460243/0/en/Caribou-Biosciences-Rep
orts-Positive-Additional-Data-from-CB-010-Allogeneic-CAR-T-Cell-Therapy-Phase-1-ANTLER-Trial-at-th
e-European-Hematology-Association-EHA-2022-Hybrid-Congress.html
[4] Genentech Announces Positive Data from Broad Blood Cancer Portfolio at European Hematology
Association Annual Meeting. Retrieved June 10, 2022,
from https://www.businesswire.com/news/home/20220609005656/en
[5] Vor Bio Successfully Demonstrates Multiplex Editing of Hematopoietic Stem Cells for Next-generation
AML Treatment Presented at EHA. Retrieved June 10, 2022,
from https://ir.vorbio.com/news-releases/news-release-details/vor-bio-successfully-demonstrates-multipl
ex-editing
[6] Janssen Presents Updated Data at EHA for Teclistamab in Patients with Relapsed or Refractory
Multiple Myeloma. Retrieved June 10, 2022,
from https://www.janssen.com/janssen-presents-updated-data-eha-teclistamab-patients-relapsed-or-refr
actory-multiple-myeloma
[7] AbbVie Presents Investigational Navitoclax Preliminary Data in JAK Inhibitor Naïve Myelofibrosis
Patients. Retrieved June 10, 2022,
from https://news.abbvie.com/news/press-releases/abbvie-presents-investigational-navitoclax-preliminar
y-data-in-jak-inhibitor-nave-myelofibrosis-patients.htm

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