Former antibody technology pioneer $2.5 billion market value "zero", misunderstood counterattack story

There has always been no shortage of outlets in the field of innovative drugs
.

Also understandable
.

In this context, once a biotech discovers a new continent, it may quickly become the focus of the
market.

Such is the case
with the American biotech company Cytomx.

In 2013, Cytomx was officially unveiled
with its former antibody technology Probody.

Not only can it increase the treatment window of existing drugs, reduce toxicity and increase efficiency; It can bring the dawn
of medicine to the unfinished drug targets.

It is precisely because of this disruptive innovation technology that Cytomx has been sought after by many large pharmaceutical companies and favored by capital, with a market value of 2.

However, the outlet not only needs the support of the "story", but also depends on the result
.

In the blink of an eye, a decade has passed, and Cytomx has not opened the way for immunotherapy to crack the mountain and bring safety and effect bonuses
as previously expected.

Both pharmaceutical companies and capital are gradually losing patience
.

After a decade of struggle, Cytomx is back to square one
.

/ 01 /

Pre-gestational antibody technology, Cytomx exploded

Immunotherapy has long been a hot area
of innovative drug development.

Therefore, many pharmaceutical companies are committed to finding a feasible technology to minimize
the side effects of immunotherapy.

In 2013, Cytomx proposed the concept
of Probody, a pre-antibody technology platform, based on Prodrug and Antibody.

Antibodies are not unfamiliar to everyone, but many people may be confused when it comes to antibodies
.

So, how do proteolytic enzymes activate the activity of pre-antibody drugs?

This is to start from its structure, the former antibody drug consists of three parts: an occlusive peptide bound to the N-terminal of the antibody light chain, a protease that connects the occlusive peptide to the antibody can cut the joint, and an antibody with anticancer
effect.

The role of both the hyphenon and the antibody is well understood, with an emphasis on masking the peptide
.
Occlusion peptides act like shields and protect the activity
of antibodies.
Under the protection of the occlusion peptide, the antibody cannot bind to the antigen in normal tissues, and the off-target effect will not occur, bringing side effects
.

However, after arriving at the tumor microenvironment, things are different
.
Because the tumor microenvironment contains many proteases, it is possible to cut the "bridge" linker between the occlusion peptide and the antibody, thereby removing the antibody "camouflage" and being able to bind to the receptor on the tumor
.

In theory, pre-antibody drugs will only play a role in the tumor microenvironment, and naturally avoid the side effects
of immune drugs to the greatest extent.
This can not only empower the antibodies that have been formed, but also bring light
to the unfinished targets.

In the field of immunotherapy, the reason why individual targets are not medicated is because the content in normal tissues is high, so it is difficult to balance
toxic side effects and efficacy.
But with the pre-antibody technology, there is the possibility
of becoming a drug.

For example, CD166, because it is widely present in cancer cells and normal tissues, has not been regarded as an ideal drug target
.

Today, borrowing pre-antibody technology can block CD166 from functioning in normal tissues
.
Therefore, CD166 also has the possibility of becoming a drug, and Cytomx developed the pre-antibody ADC CX-2009
for CD166.

What is more famous is that pre-antibody drugs do not limit the types of drugs of action, from monoclonal antibodies to ADCs and even to CAR-T, this technology can be used, which can be called immunotherapy drugs
.

This has attracted the attention
of many international pharmaceutical companies.
Although this technology is still in the early stage of clinical practice, large pharmaceutical companies have paid deposits first
.
Over the past few years, Pfizer, Bristol-Myers Squibb, Amgen, and AbbVie have all been partners
with Cytomx.

Many domestic pharmaceutical companies have also followed up, such as Tianyan Pharmaceutical and Zhangjiang Biologics, which are engaged in the research and development
of pre-antibody drugs.

In full view, Cytomx's market value soared, hitting $2.
5 billion in March 2018.

Unfortunately, Cytomx's highlight moments come and go quickly
.

/ 02 /

From sweet to Cow Lady, why did Cytomx fall?

Innovative drug research and development has a "double ten" law: a billion dollars, ten years
.
This is not only a costly project, but also a long-term thing
.

However, no matter how long the cycle is, it is also necessary for pharmaceutical companies to continuously release positive information and let the market see hope
.
Cytomx failed to do that
.
This also makes Cytomx's former partners begin to choose to withdraw from this gamble
.

The first to exit was the big pharmaceutical company Pfizer
.
In March 2018, Pfizer canceled its partnership
with CytomX.
The reason may be that in the more than four years of signing the partnership, none of the projects that Cytomx and Pfizer have cooperated with have entered the clinical stage
.

Then, in February 2019, Bristol-Myers Squibb announced its retirement from the ring by abandoning three drug candidates in its previous deal with Cytomx and continuing to develop CTLA-4 monoclonal antibody
.

Big pharma and Cyotmx have broken up, making many people start to doubt
the prospects of Cytomx.
After all, if Cytomx technology has a bright future, how can a well-informed pharmaceutical company be willing to let go
.
The same is true of the fact that Cytomx shares plunged 31%
after Bristol-Myers Squibb announced the news.

Since then, the clinical data of former antibody drugs released by Cytomx seems to prove the "foresight" of these two large pharmaceutical companies
.

In December 2021, Cytomx released Phase I clinical data on the pre-antibody ADC drug CX-2029, which targeted CD71, and the results could not bear to look at directly
.

In 16 patients with advanced non-small cell lung cancer who could assess efficacy, the objective remission rate was 18.
8%, which means that it was only effective
in about 20% of patients.
This number is already uncompetitive
in the face of K drug alone.

Of the 25 patients with assessable head and neck squamous cell carcinoma, only one patient had partial remission, and the objective response rate was 4%, which was basically ineffective
.

In terms of safety, CX-2029 also does not achieve the attenuation effect as Cytomx envisions
.
In the 5 mg/kg dose group with the best effect of the drug, the incidence of adverse reactions greater than grade 3 reached 100%.

As a result, investors also voted with their feet after the clinical data was released, and Cytomx's stock price plunged 40%.

And that's just the beginning
.

On July 6 this year, Cytomxs' CD166-targeting pre-antibody ADC drug CX-2009 still failed clinically in patients with triple-negative breast cancer
.

If the ADC is inherently complex, the failure of the pre-antibody ADC is reasonable
.
Then the performance of the former antibody monoclonal antibody is surprising
.

At this year's ESMO conference, Bristol-Myers Squibb announced the primary clinical data of CTLA-4 pre-antibody monotherapy or combined with PD-1 for the treatment of advanced solid tumors, and the data was even more collapsed
.

The objective remission rate and disease control rate of 26% in the CTLA-4 pre-antibody monotherapy group were 0%; The objective response rate in the combination treatment group was 16%, and the disease control rate was 38%.

It is not difficult to see that the treatment effect of CTLA-4 pre-antibody monotherapy is minimal
.
If there is no efficacy, then the safety of the drug does not seem to be of much
significance.

After successive failures, Cytomx's stock price began to decline all the way, with only $98 million
left in its market capitalization.

This also means that Cytomx has basically lost its financing function, and must not continue to survive, abandon the research and development of its antibody drug conjugates CX-2043 and CX-2009, focus on the development of two other anti-cancer drugs, and Cytomx will lay off 40%.

A few years ago, Cytomx was the much-sought after Wall Street star, but now his life hangs on the line
.

/ 03 /

Is the story of the development of the former antibody drug finished?

Of course, this does not mean that the story of the development of the former antibody drug is over
.

The development of science and technology has always been a spiral, and new technologies and new products will never appear out of thin air, nor will they disappear out
of thin air.

The development of new technologies is a gradual process, and the development of new drugs is a process
of eliminating all difficulties and constantly moving forward.

Judging from past experience, the process will not be too easy and will not be too short
.

Take the development of ADC drugs, although ADC drug development is in full swing today, it has been a hundred years since the theory was put forward to complete success
.

In contrast, the pre-antibody technology has only been developed for ten years now, and it can be said that this technology is still very young
.

For such a new technology, it is not rational to sentence Cytomx to the "death penalty" just because of
its several failures.

What's more, it is the folding of Cytomx that makes the latecomers more aware of the problems of
pre-antibody technology.

For example, the off-target effect
of pre-antibody technology.

The release of proantibody drug shielding peptides relies on tumor-specific proteases, but if healthy tissues also contain trace amounts of proteases, then proantibody drugs may play a role in normal tissues and have off-target effects
.

Even if the drug can be released completely in the tumor, there may be some drugs that will circulate into normal tissues and still have off-target effects
.
Therefore, in the future, we need to try our best to reduce the off-target effect
.

Another example is the choice of covert peptide shielding capabilities
.

If the shielding ability of the hidden peptide is too strong, then the time to enter the microenvironment can not completely cut the shielding peptide, which will also affect the effect of the
drug.
However, if the binding ability of hidden peptides is reduced, it is easy to increase the toxicity of off-target problems, so how to find a compromise binding force is also the direction of
improvement.

In addition, there is the problem of the selection of connectors
.

Ideally, shielding peptides can be precisely cleaved in the tumor microenvironment, but it is not easy
to actually choose a suitable hymens so that they can accurately regulate the different states of closure and opening in different environments.

Knowing where the problem is and following the direction of the problem is more likely to find a solution
.
After repeated repositioning of the current route, the story of the former antibody can get back on track
.

In fact, the development of innovative drugs is like a protracted journey to fight monsters, and all the difficulties are only staged
.
The former antibody is no exception, and its story is far from the time
to shout stop.

But the example of Cytomx driving high and going low still tells us once again that the outlet of innovative drugs may come suddenly and go "unexpectedly"
.