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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5608_Библиотеки_им_академика_М_И_Перельмана.pdf
370
AN
BN
D. Y. Jackson
Fig. 12.18 Kaplan-Meier Plot of overall survival in ASCENT trial. (Source: Prescribing information, June 2022)
asp
179
MMAF
arg
278
+
H2N
O
H
N
N
O
O
H
N
-
O
O
O
H
N
HO
N
O
O
Fig. 12.19 (a) Structures of auristatins MMAE and MMAF. (b) X-ray structure of MMAF bound
to tubulin showing favorable electrostatic interactions at both N and C terminus
The small difference in structure impacts tubulin binding afnity due to the interaction of the negative charge on MMAF with Arg278 on tubulin (Fig.12.19b) [71].
The absence of a negative charge on the C-terminus of MMAE results in reduced
tubulin binding afnity and reduced potency in tubulin polymerization assays.
The negative charge on MMAF also limits membrane permeability and results in
a 200-fold decrease in cytotoxicity relative to MMAE in cell proliferation assays.
Ironically, the property that increases tubulin binding and antimitotic activity of
MMAF also decreases permeability and cytotoxicity. When the payloads are conjugated to antibodies, however the differences in permeability are insignicant and
the more potent tubulin inhibitor (MMAF) yields a more potent ADC.Once released
from the ADC, MMAF accumulates inside cells to reach high local concentrations
while MMAE is able to diffuse out and enter nearby cells. The superior cell permeability of MMAE enables a “bystander effect” in that the payload is able to kill
_
12 Development ofAntibody-Drug Conjugates
371
neighboring cells in the tumor microenvironment. Unfortunately, this bystander
effect also leads to off-target toxicity and contributes to ADC toxicity.
Another interesting feature of Blenrep is the relatively stable “non cleavable”
MC linker. The MC linker is commercially available and can be attached to the
payload in a single step which simplies manufacturing (Fig. 12.20). Metabolic
studies support the “non cleavable” linker description and demonstrate that free
MMAF is not released from the ADC [72]. In fact, ADC metabolites containing
MMAF are not released until the antibody backbone is digested by lysosomal proteases and releases Cys-MC-MMAF.Researchers originally assumed that the cysteine residue was derived from the original antibody conjugation site. Subsequent
studies with radiolabeled MMAF demonstrated that the cysteine residue was actually derived from serum albumin based on sequence analysis of cysteine peptide
fragments attached to the MMAF payloads [57]. Serum albumin is the most abundant protein in plasma and happens to contain a single unpaired cysteine.
Additional experiments have conrmed that incubation of ADCs containing
maleimide linkers in human plasma results in thiol exchange of the maleimide
linker and transfer of the toxic payload to serum albumin. Once they are transferred
to albumin, the payloads are no longer tumor selective and are distributed systemically to other tissues. The reversible nature of maleimide linkers makes them prone
to exchange with other thiol-containing molecules found in serum such as glutathione and cysteine. Researchers have known about maleimide instability since before
the second ADC was approved, yet ADC companies continue to use them for conjugation. Even Kadcyla, which is conjugated via lysine, contains a maleimide group
connecting the linker to the payload instead of the antibody. The widespread use of
maleimide linkers in ADC likely contributes to the toxicity of most ADCs [50].
The rst paragraph of the prescribing information for BLENREP, Belantamab
mafodotin, reads, “BLENREP is a B-cell maturation antigen (BCMA) directed antibody and microtubule inhibitor (MMAF) conjugate indicated for the treatment of
adult patients with relapsed or refractory multiple myeloma who have received at
least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome
inhibitor, and an immunomodulatory agent.” The second paragraph is a statement
that Blenrep was approved under an accelerated approval based on its response rate.
The next 16 pages are dedicated to describing a variety of potential side effects and
adverse reactions ranging from ocular disorders to respiratory tract infections. The
multiple side-effects might be considered acceptable by some patients and their
S S
S S
S S
1) reduction
S S
TCEP
S S
SH
HS
SH
SH
2) conjugation
S S
MC-MMAF
S S
SH
HS
HS
S
S S
O
N
O
x 4
O
N
O
N
N
N
O
O
O
O
H
N
O
O
O
Fig. 12.20 Synthesis of Blenrep via partial reduction and conjugation to yield a heterogeneous
ADC with four payloads perantibody
372
D. Y. Jackson
physicians if BLENREP demonstrated signicant efcacy. The accelerated approval
of Blenrep was based on a clinical trial of 97 patients with relapsed or refractory
multiple myeloma (Table12.5) [70]. The overall response rate of 31% with only one
complete response was considered sufcient benet to justify approval. Like most
clinical trials for cancer, the lack of a meaningful control group makes it difcult to
assess the real benet of treatment.
12.8.10 Zynlonta
Zynlonta (aka loncastuximab tesirine-lpyl) was developed by ADC therapeutics and
approved in April of 2021. It is a CD19-specic ADC for the treatment of patients
with relapsed or refractory large B-cell lymphoma. Like most ADCs, Zynlonta was
granted accelerated approval by the FDA based on a relatively small data set of 145
patients. In a clinical trial known as LOTIS-2, Zynlonta demonstrated a 48% overall
response in DLBCL patients with complete responses observed in 24% of patients.
These results sound impressive, however, the median response duration is only
10months which means patients are likely to be back in the hospital in less than a
year. Zynlonta is also safer than most other ADCs with a mortality rate of only 2%.
As more data become available for ADCs with PBD payloads, the benets of using
Zynlonta will become clearer.
Zynlonta differs from other ADCs in that it is the rst ADC that contains a PBD
(pyrrolobenzodiazepine) dimer (aka SG3249) as its payload (Fig.12.21). The PBD
payload is an extremely toxic DNA alkylating agent that binds to the DNA minor
groove and forms DNA interstrand crosslinks leading to cell death. The released
PBD dimer (SG3199) has cytotoxic activity in the picomolar range against numerous tumor cell types and is the most potent cytotoxic payload used in an approved
ADC.The payloads are conjugated to antibody cysteines using a protease-cleavable
valine-alanine linker similar to that used for MMAE conjugation in Adcetris and
Table 12.5 Efcacy of Blenrep in DREAMM-2 clinical trial
BLENREP
N=97
Overall response rate (ORR), n (%) (97.5% CI) 30 (31%)
(21%, 43%)
Stringent complete response (sCR), n (%) 2 (2%)
Complete response (CR), n (%) 1 (1%)
Very good partial response (VGPR), n (%) 15 (15%)
Partial response (PR), n (%) 12 (12%)
Median duration of response in monthsa (range) NR [NR to NR]
Source: Prescribing information
a
NR not reached
O
12 Development ofAntibody-Drug Conjugates
373
other ADCs. A distinguishing feature of the linker used in Zynlonta is the insertion
of a polyethylene glycol (PEG) spacer that extends the PBD dimer away from the
antibody. The PBD payloads are very hydrophobic and have poor solubility in aqueous solution, which limits the number of payloads that can be conjugated perantibody. ADCs conjugated with PBD payloads are prone to aggregation and often
precipitate during conjugation. The hydrophilic PEG spacer was designed to reduce
aggregate formation and enables the conjugation of up to two PBD payloads
perantibody.
12.8.11 Tivdak
Tivdak, (aka tisotumab vedotin-tftv) is a tissue factor (TF) directed antibody-drug
conjugate for the treatment of metastatic cervical cancer. It is composed of a human
anti-TF antibody conjugated to the tubulin inhibitor, MMAE.The payload is identical to that used in Adcetris, Polivy, and Padcev and is conjugated to the antibody via
interchain cysteines to yield a heterogeneous mixture of ADC isoforms with an
average of 4 drugs perantibody (see Fig.12.8). Tivdak is the third ADC developed
by Seagen and was approved in late 2021 making it the newest FDA-approved
ADC.Approval was based on safety and efcacy data from the innovaTV 204 clinical trial with 101 patients. The results are summarized in Table12.6.
The results indicate that Tivdak demonstrated a modest 24% overall response
rate and 7% complete responses. As with other MMAE or MMAF ADCs, Tivdak
can cause severe ocular toxicity leading to vision loss and corneal ulceration.
Adverse ocular reactions occurred in 60% of patients treated with Tivdak, but most
adverse reactions were temporary and resolved when Tivdak administration was
discontinued. Other adverse side effects include peripheral neuropathy (42%), hemorrhage (62%), and pneumonitis (1.3%). Fatal adverse reactions occurred in 4% of
patients and adverse reactions leading to dose interruption occurred in 47% of
patients. Again, the lack of a meaningful control group for comparison raises questions about the benets of treatment.
x 2.3
PEGspacer
S
O
N
O
O
H
N
O
cleavage site
HO
O
H
N
N
H
8
O
N
O
H
O
N
HO
H
O
N
N
H
O
O
O
lysosome
N
O
N
O
H
O
N
O
O
O
H
N
N
+
O
O
O
O
HN
+
CO
2
Fig. 12.21 Structure of Zynlonta and release of the PBD dimer upon lysosomal protease cleavage
374
Table 12.6 Efcacy results from innovaTV 204 clinical trial
Endpoint N=101
Conrmed ORR
(95% CI)
Complete response rate 7%
Partial response rate 17%
Duration of response
Median duration of response, months
(95% CI)
Source: Prescribing information, 2021
CI condence interval, NR not reached
a
Based on patients (n=24) with a response by IRC
a
24%
(15.9, 33.3)
8.3
(4.2, NR)
D. Y. Jackson
12.9 Concluding Remarks
The rst paragraph in the clinical experience section of the prescribing information
for Tivdak is a disclaimer that reads; “Because clinical trials are conducted under
widely varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another drug and
may not reect the rates observed in practice.” This statement could be applied to
most cancer drugs and highlights one of the major challenges facing the oncology
eld. How can we be certain that a drug is efcacious without proper negative control groups? Most doctors will respond to this question by saying that it would be
unethical to give cancer patients a placebo or deny them the best possible treatment
options. In reality, there are numerous patients who choose not to undergo treatment
and could therefore serve as part of a negative control group. Untreated patients
could be monitored for tumor progression, survival probability, and other relevant
endpoints that would provide a benchmark for comparison with patients who
received treatment. The problem is that patients who decline treatment are not likely
to show up for appointments even if they were available. In addition, pharmaceutical companies would rather avoid the additional cost of monitoring untreated
patients in clinical trials; perhaps because of the potential for unfavorable results.
The unusually high incidence of ADC side effects and the relatively poor
response rates offered by most ADCs, combined with the high cost of treatment, can
make it difcult to understand why so many patients (and their physicians) would
opt to undergo treatment with an ADC.I have asked this question to cancer patients
frequently and their answers usually convey a belief that there are not any better
options available. Most patients place unquestionable trust in their doctors and seldom question their recommendations for treatment. I suspect that many patients
make their decision to undergo treatment based on hope, rather than scientic data.
For these patients, clinical trial data for cancer indications are meaningless because
the trials involve too many variables or they are too complex for patients to fully
understand. A subset of patients decide not to be treated and usually never return to
the doctor’s ofce.
12 Development ofAntibody-Drug Conjugates
375
Most people know someone who has survived cancer and perhaps know someone who did it without treatment. I personally know several people, including my
father, who were diagnosed with cancer and chose to let the disease run its course.
These patients were told by their doctors that their survival was dependent upon
extensive surgery, followed by radiation and/or chemotherapy. In my father’s case,
he was diagnosed with stage 3 bladder cancer when he was 70years old. His doctor
advised him to have his bladder removed and undergo chemotherapy. He declined
both options and lived 14 more years in relative comfort until he died of a heart
attack at 84.
For cancer patients who choose to undergo chemotherapy, ADCs are a welcome
alternative to conventional chemotherapy. There are still many challenges to overcome but the steady progress of the last two decades is a promising sign that their
benet will someday outweigh the risk of treatment. The ADCs of the future will
carry payloads that do not need to be released and will therefore have better safety.
ADCs with highly stable linkers have recently appeared which suggests payload
release might not be required for some ADCs. Future ADCs will be capable of
delivering multiple payloads to improve their therapeutic window and overcome
resistance mechanisms. One undisputable truth about the current status of targeted
therapeutics is that ADCs will continue to improve and continue to bring hope to
cancer patients.
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